Mtorc1 inhibitors

ABSTRACT

Disclosed herein, inter alia, are compounds and methods of using the same for modulating the activity of mTORC1.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/126,210, filed Sep. 10, 2018, which is a continuation of U.S. patentapplication Ser. No. 15/455,727, filed Mar. 10, 2017, which is acontinuation of International Patent Application No. PCT/US2015/049693,filed Sep. 11, 2015, which claim the benefit of U.S. ProvisionalApplication No. 62,049,186, filed Sep. 11, 2014, the contents of whichare hereby incorporated herein in their entirety and for all purposes.

REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED AS AN ASCII TEXT FILE

The Sequence Listing written in file 048536-551C03US_ST25.TXT, createdon Mar. 23, 2020, 40,509 bytes, machine format IBM-PC, MS-Windowsoperating system, is hereby incorporated by reference.

BACKGROUND

The mammalian target of rapamycin (mTOR) is a serine-threonine kinaserelated to the lipid kinases of the phosphoinositide 3-kinase (PI3K)family. mTOR exists in two complexes, mTORC1¹ ² and mTORC2³ ⁴, which aredifferentially regulated, have distinct substrate specificities, and aredifferentially sensitive to rapamycin. mTORC1 integrates signals fromgrowth factor receptors with cellular nutritional status and controlsthe level of cap-dependent mRNA translation by modulating the activityof key translational components such as the cap-binding protein andoncogene eIF4E⁵.

Recently, mTOR signaling has been deciphered in increasing detail. Thediffering pharmacology of inhibitors of mTOR have been particularlyinformative. The first reported inhibitor of mTOR, Rapamycin is nowunderstood to be an incomplete inhibitor of mTORC1⁶. Rapamycin, is aselective mTORC1 inhibitor through the binding to the FK506 RapamycinBinding (FRB) domain of mTOR kinase with the aid of FK506 bindingprotein 12 (FKBP12). The FRB domain of mTOR is accessible in the mTORC1complex, but less so in the mTORC2 complex. Interestingly, the potencyof inhibitory activities against downstream substrates of mTORC1 by thetreatment of Rapamycin is known to be diverse among the mTORC1substrates. For example, Rapamycin strongly inhibits phosphorylation ofS6K and phosphorylation of the downstream ribosomal protein S6 whichcontrol ribosomal biogenesis. On the other hand, Rapamycin shows onlypartial inhibitory activity against phosphorylation of 4E-BP1, a majorregulator of eIF4E which controls the initiation of CAP-dependenttranslation. As a result, more complete inhibitors of mTORC1 signalingare of interest⁷.

Recently, a second class of “ATP-site” inhibitors of mTOR kinase, werereported⁶ ⁸. Such inhibitors have been referred to by several names(Torkinib⁶, Torin⁸, asTORi⁹, and others). This class of mTOR inhibitorwill be referred to as asTORi (ATP site TOR inhibitor). The moleculescompete with ATP, the substrate for the kinase reaction, in the activesite of the mTOR kinase (and are therefore also active site mTORinhibitors). As a result, these molecules inhibit downstreamphosphorylation against a broader range of substrates¹⁰. The asTORi alsoinhibit mTORC2, which is not inhibited by Rapamycin, since the former donot require the FRB domain to bind and inhibit mTORC2. The compoundINK128 (now termed MLN0128) is related to PP242^(6,11) and is innumerous anti-cancer Phase I and Phase II clinical trials. MLN0128 hasthe effect of blocking 4E-BP1 phosphorylation.

Although asTORi may have the effect of blocking 4E-BP1 phosphorylation,these agents may also inhibit mTORC2, which leads to a block of Aktactivation due to phosphorylation of Akt S473. This dual action on4EBP1-P and Akt-P produces a more broad acting agent. For example a doselimiting toxicity of MLN0128 in clinical trials is Grade ≥3hyperglycemia¹².

Disclosed herein, inter alia, are mTORC1 inhibitors thereby providingsolutions to these and other problems in the art.

BRIEF SUMMARY OF THE INVENTION

In an aspect is provided a compound including a monovalent active sitemTOR inhibitor covalently bound to a monovalent rapamycin or amonovalent rapamycin analog.

In another aspect is provided a pharmaceutical composition including apharmaceutically acceptable excipient and a compound, orpharmaceutically acceptable salt thereof, as described herein, includingembodiments (e.g. in an aspect, embodiment, example, figure, table, orclaim).

In an aspect is provided a method of treating a disease associated withan aberrant level of mTORC1 activity in a subject in need of suchtreatment.

In another aspect is provided a method of treating an mTORC1activity-associated disease in a subject in need of such treatment, themethod including administering a compound, or a pharmaceuticallyacceptable salt thereof, as described herein, including embodiments(e.g. a claim, embodiment, example, table, figure, or claim).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Histogram depicting fold change (relative to vehicle control) inlive AKT^(T) and AKT^(T);4EBP1^(M) tumor cells after 24 hr treatmentwith PP242 (2.5 μM) ex vivo (n=3) (*p<0.001; n.s., no statisticalsignificance). Data are presented as the average±SEM. Treatment: leftbin: DMSO; center and right bins: PP242.

FIGS. 2A-2B. Design concept. (FIG. 2A) Overlap modeling of cocrystalstructure of mTOR catalytic domain with PP242 (MLN0128 has not beencrystalized in mTOR, but PP242 was the prototype for MLN0128 and thusserved as a model) with mTOR FRB domain with Rapamycin. Dotted linesrepresent the distance between isopropyl group of PP242 and C40-hydroxygroup of Rapamycin. (FIG. 2B) General structure of Rapamycin derivativeconjugated with asTORi.

FIGS. 3A-3B. Model of mTOR signaling inhibition. (FIG. 3A) Knowninhibitors such as Rapalog and mTOR catalytic inhibitor (asTORi). (FIG.3B) Novel Rapamycin derivatives conjugated with asTORi.

FIGS. 4A-4B. Design concept. (FIG. 4A) Overlap modeling of co-crystalstructure of mTOR catalytic domain bearing active site inhibitor PP242(4JT5) with mTOR FRB domain/rapamycin/FKBP12 (1FAP). Dotted line withnumber represents the distance (A) between isopropyl group of PP242 andC40-hydroxy group of rapamycin. (FIG. 4B) Compound design andcomputational calculation of potential energies of various cross-linker(L=methylene) length compounds.

FIGS. 5A-5B. Cell viability assays of SNU-449 Cells treated with (FIG.5A) M-1115, Rapamycin, M-1071, M-1111, and MLN0128. or (FIG. 5B)MLN0128, M-1071, or a combination of Rapamycin+ MLN0128. Legend: FIG.5A: M-1115 (squares); Rapamycin (circles); M-1071 (triangles); M-1111(squares); MLN0128 (circles); FIG. 5B: MLN0128 (circles); MLN0128+Rapamycin (1:1) (circles); M-1071 (triangles).

FIGS. 6A-6B. Cell viability assays of 786-0 Cells treated with (FIG. 6A)M-1115, Rapamycin, M-1071, M-1111, and MLN0128. or (FIG. 6B) HCT-15Cells treated with M-1115, Rapamycin, M-1071, M-1111, and MLN0128.Legend: FIG. 6A: M-1115 (squares); Rapamycin (circles); M-1071(triangles); M-1111 (squares); MLN0128 (circles). FIG. 6B: Rapamycin(circles); M-1115 (squares); M-1071 (triangles); M-1111 (squares);MLN0128 (circles).

FIG. 7. Dose dependent effects on TORC1 and TORC2 outputs for (left)M-1071, (center) M-1111, and (right) M-1115 in HCT-15 Cells.

FIGS. 8A-8B. Dose dependent effects on TORC1 and TORC2 (FIG. 8A) outputsfor MLN0128, Rapamycin, M-1071, M-1111, and M-1115 in SNU-449 Cells.(FIG. 8B) Time dependent signaling effects of MLN0128 (dose),M-1071(dose), and Rapamycin (dose), in SNU-449 Cells.

FIG. 9. In vivo effects of M-1071 on 786-0 tumor bearing mice followingsingle or multiple day dosing.

FIG. 10. Mean blood glucose levels (n=3) after drug treatment in mice.Legend: M-1077 1 mg/kg (triangle in dotted line); M-1071 3 mg/kg (circlein dashed line); M-1071 5 mg/kg (square in solid line); Rapamycin 5mg/kg (cross in solid line); MLN0128 1 mg/kg (triangle in dotted line);MLN0128 3 mg/kg (circle in dashed line); MLN0128 5 mg/kg (square insolid line); Vehicle (diamond in solid line).

FIG. 11. TORC1 and TORC2 outputs at times after washout for (left)M-1071, (center) MLN0128, and (right) Rapamycin in SNU-449 cells.

FIG. 12. Chemical drawings depicting the Rapa-LINK inhibitor M1071combining the allosteric inhibitor, rapamycin, with the ASi, MLN-0128.Compounds E1035 and E1010 combined rapamycin with the known ASi, PP242,and a PP242 derivative, MeO-PP242, respectively, as depicted.

FIGS. 13A-13B. FIG. 13A: MCF-7 cells were treated for 4 hours with E1035and M1071 before harvesting. FIG. 13B: SNU-449 cells were treated with 3hours with E1010 before harvesting. Cells were lysed and blotted for theindicated proteins. M1071 has the narrowest concentration range betweenmTORC1 and mTORC2 inhibition. The concentration range between mTORC1 andmTORC2 inhibition widens for E1035. E1010, which contains an extremelyweak ASi, only partially inhibits mTORC1.

FIGS. 14A-14B. FIG. 14A: 786-0 cells were treated for 72 hours with theindicated drugs before cell viability was measured. Legend: E1010(squares); MLN0128 (circles); Rapamycin (triangles). FIG. 14B: MCF-7cells were treated for 72 hours with the indicated drugs before cellviability was measured. Legend: E1035 (circles); M1071 (squares);Rapamycin (triangles tip up); PP242 (triangles tip down).

DETAILED DESCRIPTION A. Definitions

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight (i.e., unbranched) or branchednon-cyclic carbon chain (or carbon), or combination thereof, which maybe fully saturated, mono- or polyunsaturated and can include di- andmultivalent radicals, having the number of carbon atoms designated(i.e., C₁-C₁₀ means one to ten carbons). Examples of saturatedhydrocarbon radicals include, but are not limited to, groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, (cyclohexyl)methyl, homologs and isomers of, for example,n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkylgroup is one having one or more double bonds or triple bonds. Examplesof unsaturated alkyl groups include, but are not limited to, vinyl,2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and thehigher homologs and isomers. An alkoxy is an alkyl attached to theremainder of the molecule via an oxygen linker (—O—). An alkyl moietymay be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. Analkyl moiety may be fully saturated.

The term “alkylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkyl, asexemplified, but not limited by, —CH₂CH₂CH₂CH₂—. Typically, an alkyl (oralkylene) group will have from 1 to 24 carbon atoms, with those groupshaving 10 or fewer carbon atoms being preferred in the presentinvention. A “lower alkyl” or “lower alkylene” is a shorter chain alkylor alkylene group, generally having eight or fewer carbon atoms. Theterm “alkenylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkene.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched non-cyclicchain, or combinations thereof, including at least one carbon atom andat least one heteroatom selected from the group consisting of O, N, P,Si, and S, and wherein the nitrogen and sulfur atoms may optionally beoxidized, and the nitrogen heteroatom may optionally be quaternized. Theheteroatom(s) 0, N, P, S, and Si may be placed at any interior positionof the heteroalkyl group or at the position at which the alkyl group isattached to the remainder of the molecule. Examples include, but are notlimited to: —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CHO—CH₃,—Si(CH₃)₃, —CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, —O—CH₃, —O—CH₂—CH₃, and—CN. Up to two or three heteroatoms may be consecutive, such as, forexample, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. A heteroalkyl moiety mayinclude one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moietymay include two optionally different heteroatoms (e.g., O, N, S, Si, orP). A heteroalkyl moiety may include three optionally differentheteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may includefour optionally different heteroatoms (e.g., O, N, S, Si, or P). Aheteroalkyl moiety may include five optionally different heteroatoms(e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8optionally different heteroatoms (e.g., O, N, S, Si, or P).

Similarly, the term “heteroalkylene,” by itself or as part of anothersubstituent, means, unless otherwise stated, a divalent radical derivedfrom heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—. As describedabove, heteroalkyl groups, as used herein, include those groups that areattached to the remainder of the molecule through a heteroatom, such as—C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and/or —SO₂R′. Where“heteroalkyl” is recited, followed by recitations of specificheteroalkyl groups, such as —NR′R″ or the like, it will be understoodthat the terms heteroalkyl and —NR′R″ are not redundant or mutuallyexclusive. Rather, the specific heteroalkyl groups are recited to addclarity. Thus, the term “heteroalkyl” should not be interpreted hereinas excluding specific heteroalkyl groups, such as —NR′R″ or the like.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, mean, unless otherwise stated,non-aromatic cyclic versions of “alkyl” and “heteroalkyl,” respectively,wherein the carbons making up the ring or rings do not necessarily needto be bonded to a hydrogen due to all carbon valencies participating inbonds with non-hydrogen atoms. Additionally, for heterocycloalkyl, aheteroatom can occupy the position at which the heterocycle is attachedto the remainder of the molecule. Examples of cycloalkyl include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl,3-hydroxy-cyclobut-3-enyl-1,2, dione, 1H-1,2,4-triazolyl-5(4H)-one,4H-1,2,4-triazolyl, and the like. Examples of heterocycloalkyl include,but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl,tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A“cycloalkylene” and a “heterocycloalkylene,” alone or as part of anothersubstituent, means a divalent radical derived from a cycloalkyl andheterocycloalkyl, respectively. A heterocycloalkyl moiety may includeone ring heteroatom (e.g., O, N, S, Si, or P). A heterocycloalkyl moietymay include two optionally different ring heteroatoms (e.g., O, N, S,Si, or P). A heterocycloalkyl moiety may include three optionallydifferent ring heteroatoms (e.g., O, N, S, Si, or P). A heterocycloalkylmoiety may include four optionally different ring heteroatoms (e.g., O,N, S, Si, or P). A heterocycloalkyl moiety may include five optionallydifferent ring heteroatoms (e.g., O, N, S, Si, or P). A heterocycloalkylmoiety may include up to 8 optionally different ring heteroatoms (e.g.,O, N, S, Si, or P).

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “acyl” means, unless otherwise stated, —C(O)R where R is asubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent, which can be a single ring ormultiple rings (preferably from 1 to 3 rings) that are fused together(i.e., a fused ring aryl) or linked covalently. A fused ring aryl refersto multiple rings fused together wherein at least one of the fused ringsis an aryl ring. The term “heteroaryl” refers to aryl groups (or rings)that contain at least one heteroatom such as N, O, or S, wherein thenitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. Thus, the term “heteroaryl” includesfused ring heteroaryl groups (i.e., multiple rings fused togetherwherein at least one of the fused rings is a heteroaromatic ring). A5,6-fused ring heteroarylene refers to two rings fused together, whereinone ring has 5 members and the other ring has 6 members, and wherein atleast one ring is a heteroaryl ring. Likewise, a 6,6-fused ringheteroarylene refers to two rings fused together, wherein one ring has 6members and the other ring has 6 members, and wherein at least one ringis a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to tworings fused together, wherein one ring has 6 members and the other ringhas 5 members, and wherein at least one ring is a heteroaryl ring. Aheteroaryl group can be attached to the remainder of the moleculethrough a carbon or heteroatom. Non-limiting examples of aryl andheteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl,4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl,5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl,5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and6-quinolyl. Substituents for each of the above noted aryl and heteroarylring systems are selected from the group of acceptable substituentsdescribed below. An “arylene” and a “heteroarylene,” alone or as part ofanother substituent, mean a divalent radical derived from an aryl andheteroaryl, respectively. Non-limiting examples of aryl and heteroarylgroups include pyridinyl, pyrimidinyl, thiophenyl, thienyl, furanyl,indolyl, benzoxadiazolyl, benzodioxolyl, benzodioxanyl, thianaphthanyl,pyrrolopyridinyl, indazolyl, quinolinyl, quinoxalinyl, pyridopyrazinyl,quinazolinonyl, benzoisoxazolyl, imidazopyridinyl, benzofuranyl,benzothienyl, benzothiophenyl, phenyl, naphthyl, biphenyl, pyrrolyl,pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl,furylthienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl,benzimidazolyl, isoquinolyl, thiadiazolyl, oxadiazolyl, pyrrolyl,diazolyl, triazolyl, tetrazolyl, benzothiadiazolyl, isothiazolyl,pyrazolopyrimidinyl, pyrrolopyrimidinyl, benzotriazolyl, benzoxazolyl,or quinolyl. The examples above may be substituted or unsubstituted anddivalent radicals of each heteroaryl example above are non-limitingexamples of heteroarylene. A heteroaryl moiety may include one ringheteroatom (e.g., O, N, or S). A heteroaryl moiety may include twooptionally different ring heteroatoms (e.g., O, N, or S). A heteroarylmoiety may include three optionally different ring heteroatoms (e.g., O,N, or S). A heteroaryl moiety may include four optionally different ringheteroatoms (e.g., O, N, or S). A heteroaryl moiety may include fiveoptionally different ring heteroatoms (e.g., O, N, or S). An aryl moietymay have a single ring. An aryl moiety may have two optionally differentrings. An aryl moiety may have three optionally different rings. An arylmoiety may have four optionally different rings. A heteroaryl moiety mayhave one ring. A heteroaryl moiety may have two optionally differentrings. A heteroaryl moiety may have three optionally different rings. Aheteroaryl moiety may have four optionally different rings. A heteroarylmoiety may have five optionally different rings.

A fused ring heterocyloalkyl-aryl is an aryl fused to aheterocycloalkyl. A fused ring heterocycloalkyl-heteroaryl is aheteroaryl fused to a heterocycloalkyl. A fused ringheterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl.A fused ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkylfused to another heterocycloalkyl. Fused ring heterocycloalkyl-aryl,fused ring heterocycloalkyl-heteroaryl, fused ringheterocycloalkyl-cycloalkyl, or fused ringheterocycloalkyl-heterocycloalkyl may each independently beunsubstituted or substituted with one or more of the substitutentsdescribed herein.

The term “oxo,” as used herein, means an oxygen that is double bonded toa carbon atom.

The term “alkylsulfonyl,” as used herein, means a moiety having theformula —S(O₂)—R′, where R′ is a substituted or unsubstituted alkylgroup as defined above. R′ may have a specified number of carbons (e.g.,“C₁-C₄ alkylsulfonyl”).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,”, “cycloalkyl”,“heterocycloalkyl”, “aryl,” and “heteroaryl”) includes both substitutedand unsubstituted forms of the indicated radical. Preferred substituentsfor each type of radical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R″′, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R″′)═NR″″,—NR—C(NR′R″)═NR″′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R′,—ONR′R″, —NR′C═(O)NR″NR″′R″″, —CN, —NO₂, in a number ranging from zeroto (2m′+1), where m′ is the total number of carbon atoms in suchradical. R, R′, R″, R″′, and R″″ each preferably independently refer tohydrogen, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl (e.g., aryl substituted with 1-3halogens), substituted or unsubstituted heteroaryl, substituted orunsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups.When a compound of the invention includes more than one R group, forexample, each of the R groups is independently selected as are each R′,R″, R″′, and R″″ group when more than one of these groups is present.When R′ and R″ are attached to the same nitrogen atom, they can becombined with the nitrogen atom to form a 4-, 5-, 6-, or 7-memberedring. For example, —NR′R″ includes, but is not limited to,1-pyrrolidinyl and 4-morpholinyl. From the above discussion ofsubstituents, one of skill in the art will understand that the term“alkyl” is meant to include groups including carbon atoms bound togroups other than hydrogen groups, such as haloalkyl (e.g., —CF₃ and—CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and thelike).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for example: —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R″′,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O) NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R″′, —NR″C(O)₂R′, —NR—C(NR′R″R″′)═NR″″, —NR—C(NR′R″)═NR″′,—S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R″′, —ONR′R″,—NR′C═(O)NR″NR″′R″″, —CN, —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy,and fluoro(C₁-C₄)alkyl, in a number ranging from zero to the totalnumber of open valences on the aromatic ring system; and where R′, R″,R″′, and R″″ are preferably independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl. When a compound of theinvention includes more than one R group, for example, each of the Rgroups is independently selected as are each R′, R″, R″′, and R″″ groupswhen more than one of these groups is present.

Two or more substituents may optionally be joined to form aryl,heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-calledring-forming substituents are typically, though not necessarily, foundattached to a cyclic base structure. In one embodiment, the ring-formingsubstituents are attached to adjacent members of the base structure. Forexample, two ring-forming substituents attached to adjacent members of acyclic base structure create a fused ring structure. In anotherembodiment, the ring-forming substituents are attached to a singlemember of the base structure. For example, two ring-forming substituentsattached to a single member of a cyclic base structure create aspirocyclic structure. In yet another embodiment, the ring-formingsubstituents are attached to non-adjacent members of the base structure.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally form a ring of the formula -T-C(O)—(CRR′)_(q)—U—, whereinT and U are independently —NR—, —O—, —CRR′—, or a single bond, and q isan integer of from 0 to 3. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula -A-(CH₂)_(r)—B—, wherein A and B areindependently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′—, or asingle bond, and r is an integer of from 1 to 4. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —(CRR′)_(s)—X′—(C″R″R′″)_(d)—, where s and d are independentlyintegers of from 0 to 3, and X′ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituents R, R′, R″, and R″′ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

As used herein, the terms “heteroatom” or “ring heteroatom” are meant toinclude, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), andsilicon (Si).

A substituent group, as used herein, may be a group selected from thefollowing moieties:

-   -   (A) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,        —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,        —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃,        —OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl,        unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,        unsubstituted aryl, unsubstituted heteroaryl, and    -   (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, substituted with at least one substituent selected        from:        -   (i) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,            —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,            —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃,            —OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl,            unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,            unsubstituted aryl, unsubstituted heteroaryl, and        -   (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,            heteroaryl, substituted with at least one substituent            selected from:            -   (a) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,                —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,                —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H,                —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, unsubstituted alkyl,                unsubstituted heteroalkyl, unsubstituted cycloalkyl,                unsubstituted heterocycloalkyl, unsubstituted aryl,                unsubstituted heteroaryl, and            -   (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,                aryl, heteroaryl, substituted with at least one                substituent selected from: oxo, halogen, —CF₃, —CN, —OH,                —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,                —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,                —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,                unsubstituted alkyl, unsubstituted heteroalkyl,                unsubstituted cycloalkyl, unsubstituted                heterocycloalkyl, unsubstituted aryl, unsubstituted                heteroaryl.

A “size-limited substituent” or “size-limited substituent group,” asused herein, means a group selected from all of the substituentsdescribed above for a “substituent group,” wherein each substituted orunsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl.

A “lower substituent” or “lower substituent group,” as used herein,means a group selected from all of the substituents described above fora “substituent group,” wherein each substituted or unsubstituted alkylis a substituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl.

In some embodiments, each substituted group described in the compoundsherein is substituted with at least one substituent group. Morespecifically, in some embodiments, each substituted alkyl, substitutedheteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl,substituted aryl, substituted heteroaryl, substituted alkylene,substituted heteroalkylene, substituted cycloalkylene, substitutedheterocycloalkylene, substituted arylene, and/or substitutedheteroarylene described in the compounds herein are substituted with atleast one substituent group. In other embodiments, at least one or allof these groups are substituted with at least one size-limitedsubstituent group. In other embodiments, at least one or all of thesegroups are substituted with at least one lower substituent group.

In other embodiments of the compounds herein, each substituted orunsubstituted alkyl may be a substituted or unsubstituted C₁-C₂₀ alkyl,each substituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl. In someembodiments of the compounds herein, each substituted or unsubstitutedalkylene is a substituted or unsubstituted C₁-C₂₀ alkylene, eachsubstituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 20 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₈cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 8 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 10 membered heteroarylene.

In some embodiments, each substituted or unsubstituted alkyl is asubstituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and/or each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl. In some embodiments, each substituted orunsubstituted alkylene is a substituted or unsubstituted C₁-C₈ alkylene,each substituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 8 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₇cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 7 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 9 membered heteroarylene. In someembodiments, the compound is a chemical species set forth in theExamples section, figures, or tables below.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds that are prepared with relatively nontoxic acidsor bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galactunoric acids and thelike (see, e.g., Berge et al., Journal of Pharmaceutical Science 66:1-19(1977)). Certain specific compounds of the present invention containboth basic and acidic functionalities that allow the compounds to beconverted into either base or acid addition salts. Otherpharmaceutically acceptable carriers known to those of skill in the artare suitable for the present invention. Salts tend to be more soluble inaqueous or other protonic solvents than are the corresponding free baseforms. In other cases, the preparation may be a lyophilized powder in 1mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH range of 4.5to 5.5, that is combined with buffer prior to use.

Thus, the compounds of the present invention may exist as salts, such aswith pharmaceutically acceptable acids. The present invention includessuch salts. Examples of such salts include hydrochlorides,hydrobromides, sulfates, methanesulfonates, nitrates, maleates,acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates,(−)-tartrates, or mixtures thereof including racemic mixtures),succinates, benzoates, and salts with amino acids such as glutamic acid.These salts may be prepared by methods known to those skilled in theart.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents.

Provided herein are agents (e.g. compounds, drugs, therapeutic agents)that may be in a prodrug form. Prodrugs of the compounds describedherein are those compounds that readily undergo chemical changes underselect physiological conditions to provide the final agents (e.g.compounds, drugs, therapeutic agents). Additionally, prodrugs can beconverted to agents (e.g. compounds, drugs, therapeutic agents) bychemical or biochemical methods in an ex vivo environment. Prodrugsdescribed herein include compounds that readily undergo chemical changesunder select physiological conditions to provide agents (e.g. compounds,drugs, therapeutic agents) to a biological system (e.g. in a subject, ina cell, in the extracellular space near a cell).

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of thepresent invention.

As used herein, the term “salt” refers to acid or base salts of thecompounds used in the methods of the present invention. Illustrativeexamples of acceptable salts are mineral acid (hydrochloric acid,hydrobromic acid, phosphoric acid, and the like) salts, organic acid(acetic acid, propionic acid, glutamic acid, citric acid and the like)salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like)salts.

Certain compounds of the present invention possess asymmetric carbonatoms (optical or chiral centers) or double bonds; the enantiomers,racemates, diastereomers, tautomers, geometric isomers, stereoisometricforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers areencompassed within the scope of the present invention. The compounds ofthe present invention do not include those which are known in art to betoo unstable to synthesize and/or isolate. The present invention ismeant to include compounds in racemic and optically pure forms.Optically active (R)- and (S)-, or (D)- and (L)-isomers may be preparedusing chiral synthons or chiral reagents, or resolved using conventionaltechniques. When the compounds described herein contain olefinic bondsor other centers of geometric asymmetry, and unless specified otherwise,it is intended that the compounds include both E and Z geometricisomers.

As used herein, the term “isomers” refers to compounds having the samenumber and kind of atoms, and hence the same molecular weight, butdiffering in respect to the structural arrangement or configuration ofthe atoms.

The term “tautomer,” as used herein, refers to one of two or morestructural isomers which exist in equilibrium and which are readilyconverted from one isomeric form to another. It will be apparent to oneskilled in the art that certain compounds of this invention may exist intautomeric forms, all such tautomeric forms of the compounds beingwithin the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I), or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areencompassed within the scope of the present invention.

The symbol “

” denotes the point of attachment of a chemical moiety to the remainderof a molecule or chemical formula.

The terms “a” or “an,” as used in herein means one or more. In addition,the phrase “substituted with a[n],” as used herein, means the specifiedgroup may be substituted with one or more of any or all of the namedsubstituents. For example, where a group, such as an alkyl or heteroarylgroup, is “substituted with an unsubstituted C₁-C₂₀ alkyl, orunsubstituted 2 to 20 membered heteroalkyl,” the group may contain oneor more unsubstituted C₁-C₂₀ alkyls, and/or one or more unsubstituted 2to 20 membered heteroalkyls. Moreover, where a moiety is substitutedwith an R substituent, the group may be referred to as “R-substituted.”Where a moiety is R-substituted, the moiety is substituted with at leastone R substituent and each R substituent is optionally different.

Descriptions of compounds of the present invention are limited byprinciples of chemical bonding known to those skilled in the art.Accordingly, where a group may be substituted by one or more of a numberof substituents, such substitutions are selected so as to comply withprinciples of chemical bonding and to give compounds which are notinherently unstable and/or would be known to one of ordinary skill inthe art as likely to be unstable under ambient conditions, such asaqueous, neutral, and several known physiological conditions. Forexample, a heterocycloalkyl or heteroaryl is attached to the remainderof the molecule via a ring heteroatom in compliance with principles ofchemical bonding known to those skilled in the art thereby avoidinginherently unstable compounds.

The terms “treating” or “treatment” refers to any indicia of success inthe treatment or amelioration of an injury, disease, pathology orcondition, including any objective or subjective parameter such asabatement; remission; diminishing of symptoms or making the injury,pathology or condition more tolerable to the patient; slowing in therate of degeneration or decline; making the final point of degenerationless debilitating; improving a patient's physical or mental well-being.The treatment or amelioration of symptoms can be based on objective orsubjective parameters; including the results of a physical examination,neuropsychiatric exams, and/or a psychiatric evaluation. For example,certain methods herein treat diseases associated with mTORC1 activity.Certain methods described herein may treat diseases associated withmTORC1 activity by inhibiting mTORC1 activity. Certain methods describedherein may treat diseases associated with mTORC1 by inhibiting mTORC1activity to a greater degree than inhibiting mTORC2 activity. Forexample, certain methods herein treat cancer. For example certainmethods herein treat cancer by decreasing a symptom of cancer. Symptomsof cancer would be known or may be determined by a person of ordinaryskill in the art. For example, certain methods herein treat anautoimmune disease. For example certain methods herein treat anautoimmune disease by decreasing a symptom of the autoimmune disease.Symptoms of an autoimmune disease would be known or may be determined bya person of ordinary skill in the art. For example, certain methodsherein treat an inflammatory disease. For example certain methods hereintreat an inflammatory disease by decreasing a symptom of theinflammatory disease. Symptoms of an inflammatory disease would be knownor may be determined by a person of ordinary skill in the art. Forexample, certain methods herein treat a neurodegenerative disease. Forexample certain methods herein treat a neurodegenerative disease bydecreasing a symptom of the neurodegenerative disease. Symptoms of aneurodegenerative disease would be known or may be determined by aperson of ordinary skill in the art. For example, certain methods hereintreat a metabolic disease. For example certain methods herein treat ametabolic disease by decreasing a symptom of the metabolic disease.Symptoms of a metabolic disease would be known or may be determined by aperson of ordinary skill in the art. For example, certain methods hereintreat transplant rejection. For example certain methods herein treattransplant rejection by decreasing a symptom of transplant rejection.Symptoms of transplant rejection would be known or may be determined bya person of ordinary skill in the art. For example, certain methodsherein treat fungal infection. For example certain methods herein treatfungal infection by decreasing a symptom of fungal infection. Symptomsof fungal infection would be known or may be determined by a person ofordinary skill in the art. For example, certain methods herein treat acardiovascular disease. For example certain methods herein treat acardiovascular disease by decreasing a symptom of the cardiovasculardisease. Symptoms of a cardiovascular disease would be known or may bedetermined by a person of ordinary skill in the art. The term “treating”and conjugations thereof, include prevention of an injury, pathology,condition, or disease.

An “effective amount” is an amount sufficient to accomplish a statedpurpose (e.g. achieve the effect for which it is administered, treat adisease, reduce enzyme activity, increase enzyme activity, reduceprotein function, reduce one or more symptoms of a disease orcondition). An example of an “effective amount” is an amount sufficientto contribute to the treatment, prevention, or reduction of a symptom orsymptoms of a disease, which could also be referred to as a“therapeutically effective amount.” A “reduction” of a symptom orsymptoms (and grammatical equivalents of this phrase) means decreasingof the severity or frequency of the symptom(s), or elimination of thesymptom(s). A “prophylactically effective amount” of a drug or prodrugis an amount of a drug or prodrug that, when administered to a subject,will have the intended prophylactic effect, e.g., preventing or delayingthe onset (or reoccurrence) of an injury, disease, pathology orcondition, or reducing the likelihood of the onset (or reoccurrence) ofan injury, disease, pathology, or condition, or their symptoms. The fullprophylactic effect does not necessarily occur by administration of onedose, and may occur only after administration of a series of doses.Thus, a prophylactically effective amount may be administered in one ormore administrations. The exact amounts will depend on the purpose ofthe treatment, and will be ascertainable by one skilled in the art usingknown techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms(vols. 1-3, 1992); Lloyd, The Art, Science and Technology ofPharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999);and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003,Gennaro, Ed., Lippincott, Williams & Wilkins).

The term “associated” or “associated with” in the context of a substanceor substance activity or function associated with a disease (e.g.cancer, autoimmune disease, inflammatory disease, metabolic disease,neurodegenerative disease, fungal infection, cardiovascular disease, ortransplant rejection) means that the disease is caused by (in whole orin part), or a symptom of the disease is caused by (in whole or in part)the substance or substance activity or function. As used herein, what isdescribed as being associated with a disease, if a causative agent,could be a target for treatment of the disease. For example, a diseaseassociated with mTORC1 activity may be treated with an agent (e.g.compound as described herein) effective for decreasing the level ofmTORC1 activity.

“Control” or “control experiment” or “standard control” is used inaccordance with its plain ordinary meaning and refers to an experimentin which the subjects or reagents of the experiment are treated as in aparallel experiment except for omission of a procedure, reagent, orvariable of the experiment. In some instances, the control is used as astandard of comparison in evaluating experimental effects.

“Contacting” is used in accordance with its plain ordinary meaning andrefers to the process of allowing at least two distinct species (e.g.chemical compounds including biomolecules, or cells) to becomesufficiently proximal to react, interact or physically touch. It shouldbe appreciated, however, that the resulting reaction product can beproduced directly from a reaction between the added reagents or from anintermediate from one or more of the added reagents which can beproduced in the reaction mixture. The term “contacting” may includeallowing two species to react, interact, or physically touch, whereinthe two species may be a compound as described herein and a protein orenzyme. In some embodiments contacting includes allowing a compounddescribed herein to interact with a protein or enzyme.

As defined herein, the term “inhibition”, “inhibit”, “inhibiting” andthe like in reference to a protein-inhibitor (e.g. antagonist)interaction means negatively affecting (e.g. decreasing) the level ofactivity or function of the protein relative to the level of activity orfunction of the protein in the absence of the inhibitor. In someembodiments inhibition refers to reduction of a disease or symptoms ofdisease. Thus, inhibition may include, at least in part, partially ortotally blocking stimulation, decreasing, preventing, or delayingactivation, or inactivating, desensitizing, or down-regulating signaltransduction or enzymatic activity or the amount of a protein.

As defined herein, the term “activation”, “activate”, “activating” andthe like in reference to a protein-activator (e.g. agonist) interactionmeans positively affecting (e.g. increasing) the activity or function ofthe protein relative to the activity or function of the protein in theabsence of the activator (e.g. compound described herein). Thus,activation may include, at least in part, partially or totallyincreasing stimulation, increasing or enabling activation, oractivating, sensitizing, or up-regulating signal transduction orenzymatic activity or the amount of a protein decreased in a disease.Activation may include, at least in part, partially or totallyincreasing stimulation, increasing or enabling activation, oractivating, sensitizing, or up-regulating signal transduction orenzymatic activity or the amount of a protein.

The term “modulator” refers to a composition that increases or decreasesthe level of a target molecule or the function of a target molecule. Inembodiments, a modulator is an anti-cancer agent. In embodiments, amodulator is an anti-autoimmune disease agent. In embodiments, amodulator is an anti-inflammatory disease agent. In embodiments, amodulator is an anti-neurodegenerative disease agent. In embodiments, amodulator is an anti-metabolic disease agent. In embodiments, amodulator is an anti-transplant rejection agent. In embodiments, amodulator is an anti-fungal infection agent. In embodiments, a modulatoris an anti-cardiovascular disease agent. In embodiments, a modulator isa longevity agent. In embodiments, a modulator is a modulator of mTORC1activity. In embodiments, a modulator is an mTORC1 activity inhibitor.In embodiments, a modulator is an mTORC1 activity activator. Inembodiments, a modulator is a modulator of a signaling pathway includingmTORC1.

“Anti-cancer agent” or “anti-cancer drug” is used in accordance with itsplain ordinary meaning and refers to a composition (e.g. compound, drug,antagonist, inhibitor, modulator) having antineoplastic properties orthe ability to inhibit the growth or proliferation of cells. In someembodiments, an anti-cancer agent is a chemotherapeutic. In someembodiments, an anti-cancer agent is an agent approved by the FDA orsimilar regulatory agency of a country other than the USA, for treatingcancer. Examples of anti-cancer agents include, but are not limited to,rapamycin, rapamycin analog, bevacizumab, PP242, INK128, MLN0128,anti-androgens (e.g., Casodex, Flutamide, MDV3100, or ARN-509), MEK(e.g. MEK1, MEK2, or MEK1 and MEK2) inhibitors (e.g. XL518, CI-1040,PD035901, selumetinib/AZD6244, GSK1120212/trametinib, GDC-0973,ARRY-162, ARRY-300, AZD8330, PD0325901, U0126, PD98059, TAK-733,PD318088, AS703026, BAY 869766), alkylating agents (e.g.,cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan,mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogen mustards(e.g., mechloroethamine, cyclophosphamide, chlorambucil, meiphalan),ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa),alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., cannustine,lomusitne, semustine, streptozocin), triazenes (decarbazine)),anti-metabolites (e.g., 5-azathioprine, leucovorin, capecitabine,fludarabine, gemcitabine, pemetrexed, raltitrexed, folic acid analog(e.g., methotrexate), pyrimidine analogs (e.g., fluorouracil,floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine,thioguanine, pentostatin), etc.), plant alkaloids (e.g., vincristine,vinblastine, vinorelbine, vindesine, podophyllotoxin, paclitaxel,docetaxel, etc.), topoisomerase inhibitors (e.g., irinotecan, topotecan,amsacrine, etoposide (VP16), etoposide phosphate, teniposide, etc.),antitumor antibiotics (e.g., doxorubicin, adriamycin, daunorubicin,epirubicin, actinomycin, bleomycin, mitomycin, mitoxantrone, plicamycin,etc.), platinum-based compounds (e.g. cisplatin, oxaloplatin,carboplatin), anthracenedione (e.g., mitoxantrone), substituted urea(e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine),adrenocortical suppressant (e.g., mitotane, aminoglutethimide),epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin,doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), inhibitors ofmitogen-activated protein kinase signaling (e.g. U0126, PD98059,PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006,wortmannin, or LY294002), mTOR inhibitors, antibodies (e.g., rituxan),5-aza-2′-deoxycytidine, doxorubicin, vincristine, etoposide,gemcitabine, imatinib (Gleevec®), geldanamycin,17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), bortezomib,trastuzumab, anastrozole; angiogenesis inhibitors; antiandrogen,antiestrogen; antisense oligonucleotides; apoptosis gene modulators;apoptosis regulators; arginine deaminase; BCR/ABL antagonists; betalactam derivatives; bFGF inhibitor; bicalutamide; camptothecinderivatives; casein kinase inhibitors (ICOS); clomifene analogues;cytarabine dacliximab; dexamethasone; estrogen agonists; estrogenantagonists; etanidazole; etoposide phosphate; exemestane; fadrozole;finasteride; fludarabine; fluorodaunorunicin hydrochloride; gadoliniumtexaphyrin; gallium nitrate; gelatinase inhibitors; gemcitabine;glutathione inhibitors; hepsulfam; immunostimulant peptides;insulin-like growth factor-1 receptor inhibitor; interferon agonists;interferons; interleukins; letrozole; leukemia inhibiting factor;leukocyte alpha interferon; leuprolide+estrogen+progesterone;leuprorelin; matrilysin inhibitors; matrix metalloproteinase inhibitors;MIF inhibitor; mifepristone; mismatched double stranded RNA; monoclonalantibody; mycobacterial cell wall extract; nitric oxide modulators;oxaliplatin; panomifene; pentrozole; phosphatase inhibitors; plasminogenactivator inhibitor; platinum complex; platinum compounds; prednisone;proteasome inhibitors; protein A-based immune modulator; protein kinaseC inhibitor; protein tyrosine phosphatase inhibitors; purine nucleosidephosphorylase inhibitors; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; ribozymes; signal transductioninhibitors; signal transduction modulators; single chain antigen-bindingprotein; stem cell inhibitor; stem-cell division inhibitors; stromelysininhibitors; synthetic glycosaminoglycans; tamoxifen methiodide;telomerase inhibitors; thyroid stimulating hormone; translationinhibitors; tyrosine kinase inhibitors; urokinase receptor antagonists;steroids (e.g., dexamethasone), finasteride, aromatase inhibitors,gonadotropin-releasing hormone agonists (GnRH) such as goserelin orleuprolide, adrenocorticosteroids (e.g., prednisone), progestins (e.g.,hydroxyprogesterone caproate, megestrol acetate, medroxyprogesteroneacetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol),antiestrogen (e.g., tamoxifen), androgens (e.g., testosteronepropionate, fluoxymesterone), antiandrogen (e.g., flutamide),immunostimulants (e.g., Bacillus Calmette-Guérin (BCG), levamisole,interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g.,anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonalantibodies), immunotoxins (e.g., anti-CD33 monoclonalantibody-calicheamicin conjugate, anti-CD22 monoclonalantibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy(e.g., anti-CD20 monoclonal antibody conjugated to ¹¹¹In, ⁹⁰Y, or ¹³¹I,etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin,epirubicin, topotecan, itraconazole, vindesine, cerivastatin,vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan,clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib,gefitinib, EGFR inhibitors, epidermal growth factor receptor(EGFR)-targeted therapy or therapeutic (e.g. gefitinib (Iressa™),erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™),panitumumab (Vectibix™), vandetanib (Caprelsa™), afatinib/BIBW2992,CI-1033/canertinib, neratinib/HKI-272, CP-724714, TAK-285, AST-1306,ARRY334543, ARRY-380, AG-1478, dacomitinib/PF299804, OSI-420/desmethylerlotinib, AZD8931, AEE788, pelitinib/EKB-569, CUDC-101, WZ8040, WZ4002,WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib,sunitinib, dasatinib, pyrrolo benzodiazepines (e.g. tomaymycin),carboplatin, CC-1065 and CC-1065 analogs including amino-CBIs, nitrogenmustards (such as chlorambucil and melphalan), dolastatin and dolastatinanalogs (including auristatins: eg. monomethyl auristatin E),anthracycline antibiotics (such as doxorubicin, daunorubicin, etc.),duocarmycins and duocarmycin analogs, enediynes (such asneocarzinostatin and calicheamicins), leptomycin derivaties,maytansinoids and maytansinoid analogs (e.g. mertansine), methotrexate,mitomycin C, taxoids, vinca alkaloids (such as vinblastine andvincristine), epothilones (e.g. epothilone B), camptothecin and itsclinical analogs topotecan and irinotecan, INK128, PP242, PP121,MLN0128, AZD8055, AZD2014, NVP-BEZ235, BGT226, SF1126, Torin 1, Torin 2,WYE 687, WYE 687 salt (e.g., hydrochloride), PF04691502, PI-103, CC-223,OSI-027, XL388, KU-0063794, GDC-0349, PKI-587, rapamycin, deforolimus(AP23573, MK-8669, ridaforolimus), temsirolimus (CCI-779), ABT478,everolimus (RAD001) or the like.

“Chemotherapeutic” or “chemotherapeutic agent” is used in accordancewith its plain ordinary meaning and refers to a chemical composition orcompound having antineoplastic properties or the ability to inhibit thegrowth or proliferation of cells.

“Patient” or “subject in need thereof” or “subject” refers to a livingorganism suffering from or prone to a disease or condition that can betreated by administration of a compound or pharmaceutical composition orby a method, as provided herein. Non-limiting examples include humans,other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows,deer, and other non-mammalian animals. In some embodiments, a patient ishuman. In some embodiments, a subject is human.

“Disease” or “condition” refer to a state of being or health status of apatient or subject capable of being treated with a compound,pharmaceutical composition, or method provided herein. In someembodiments, the disease is a disease having the symptom of cellhyperproliferation. In some embodiments, the disease is a disease havingthe symptom of an aberrant level of mTORC1 activity. In someembodiments, the disease is a disease having the symptom of an aberrantlevel of mTORC1 pathway activity. In some embodiments, the disease is adisease associated with mTORC1 activity. In some embodiments, thedisease is a disease associated with mTORC1 pathway activity. In someembodiments, the disease is a cancer. In some embodiments, the diseaseis an autoimmune disease. In some embodiments, the disease is aneurodegenerative disease. In some embodiments, the disease is ametabolic disease. In some embodiments, the disease is an inflammatorydisease. In some embodiments, the disease is transplant rejection. Insome embodiments, the disease is fungal infection. In some embodiments,the disease is a cardiovascular disease. In some further instances,“cancer” refers to human cancers and carcinomas, sarcomas,adenocarcinomas, lymphomas, leukemias, etc., including solid andlymphoid cancers, kidney, breast, lung, bladder, colon, ovarian,prostate, pancreas, stomach, brain, head and neck, skin, uterine,testicular, glioma, esophagus, and liver cancer, includinghepatocarcinoma, lymphoma, including B-acute lymphoblastic lymphoma,non-Hodgkin's lymphomas (e.g., Burkitt's, Small Cell, and Large Celllymphomas), Hodgkin's lymphoma, leukemia (including AML, ALL, and CML),or multiple myeloma. In embodiments, the disease is multiple myeloma. Inembodiments, the disease is breast cancer. In embodiments, the diseaseis triple negative breast cancer. In embodiments, a disease that may betreated with a compound, pharmaceutical composition, or method describedherein is Organ or tissue transplant rejection (e.g. heart, lung,combined heart-lung, liver, kidney, pancreatic, skin or cornealtransplants; graft-versus-host disease), Restenosis, Hamartoma syndromes(e.g., tuberous sclerosis or Cowden Disease), Lymphangioleiomyomatosis,Retinitis pigmentosis, encephalomyelitis, insulin-dependent diabetesmellitus, lupus, dermatomyositis, arthritis, rheumatic diseases,Steroid-resistant acute Lymphoblastic Leukemia, fibrosis, scleroderma,pulmonary fibrosis, renal fibrosis, cystic fibrosis, Pulmonaryhypertension, Multiple sclerosis, VHL syndrome, Carney complex, Familialadenonamtous polyposis, Juvenile polyposis syndrome, Birt-Hogg-Dukesyndrome, Familial hypertrophic cardiomyopathy, Wolf-Parkinson-Whitesyndrome, Parkinson's disease, Huntingtin's disease, Alzheimer'sdisease, dementias caused by tau mutations, spinocerebellar ataxia type3, motor neuron disease caused by SOD1 mutations, neuronal ceroidlipofucinoses/Batten disease (pediatric neurodegeneration), wet maculardegeneration, dry macular degeneration, muscle wasting (atrophy,cachexia), myopathies (e.g., Danon's disease), bacterial infection,viral infection, M. tuberculosis, group A streptococcus, HSV type I, HIVinfection, Neurofibromatosis (e.g., Neurofibromatosis type 1), orPeutz-Jeghers syndrome.

As used herein, the term “cancer” refers to all types of cancer,neoplasm or malignant tumors found in mammals (e.g. humans), includingleukemia, carcinomas and sarcomas. Exemplary cancers that may be treatedwith a compound or method provided herein include cancer of theprostate, thyroid, endocrine system, brain, breast, cervix, colon, head& neck, liver, kidney, lung, non-small cell lung, melanoma,mesothelioma, ovary, sarcoma, stomach, uterus, Medulloblastoma,colorectal cancer, pancreatic cancer. Additional examples may include,Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma,neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer,rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia,primary brain tumors, malignant pancreatic insulanoma, malignantcarcinoid, urinary bladder cancer, premalignant skin lesions, testicularcancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer,genitourinary tract cancer, malignant hypercalcemia, endometrial cancer,adrenal cortical cancer, neoplasms of the endocrine or exocrinepancreas, medullary thyroid cancer, medullary thyroid carcinoma,melanoma, colorectal cancer, papillary thyroid cancer, hepatocellularcarcinoma, or prostate cancer.

The term “leukemia” refers broadly to progressive, malignant diseases ofthe blood-forming organs and is generally characterized by a distortedproliferation and development of leukocytes and their precursors in theblood and bone marrow. Leukemia is generally clinically classified onthe basis of (1) the duration and character of the disease-acute orchronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid(lymphogenous), or monocytic; and (3) the increase or non-increase inthe number of aberrant cells in the blood-leukemic or aleukemic(subleukemic). Exemplary leukemias that may be treated with a compoundor method provided herein include, for example, acute nonlymphocyticleukemia, chronic lymphocytic leukemia, acute granulocytic leukemia,chronic granulocytic leukemia, acute promyelocytic leukemia, adultT-cell leukemia, aleukemic leukemia, a leukocythemic leukemia,basophylic leukemia, blast cell leukemia, bovine leukemia, chronicmyelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilicleukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia,hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia,acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia,lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia,lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia,megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia,myeloblastic leukemia, myelocytic leukemia, myeloid granulocyticleukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cellleukemia, multiple myeloma, plasmacytic leukemia, promyelocyticleukemia, Rieder cell leukemia, Schilling's leukemia, stem cellleukemia, subleukemic leukemia, or undifferentiated cell leukemia.

The term “sarcoma” generally refers to a tumor which is made up of asubstance like the embryonic connective tissue and is generally composedof closely packed cells embedded in a fibrillar or homogeneoussubstance. Sarcomas that may be treated with a compound or methodprovided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma,melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adiposesarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma,botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma,Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing'ssarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma,granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmentedhemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma,immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma,Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymomasarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma,serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma.

The term “melanoma” is taken to mean a tumor arising from themelanocytic system of the skin and other organs. Melanomas that may betreated with a compound or method provided herein include, for example,acral-lentiginous melanoma, amelanotic melanoma, benign juvenilemelanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma,juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodularmelanoma, subungal melanoma, or superficial spreading melanoma.

The term “carcinoma” refers to a malignant new growth made up ofepithelial cells tending to infiltrate the surrounding tissues and giverise to metastases. Exemplary carcinomas that may be treated with acompound or method provided herein include, for example, medullarythyroid carcinoma, familial medullary thyroid carcinoma, acinarcarcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cysticcarcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolarcarcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinomabasocellulare, basaloid carcinoma, basosquamous cell carcinoma,bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogeniccarcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorioniccarcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma,cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum,cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma,carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoidcarcinoma, carcinoma epitheliale adenoides, exophytic carcinoma,carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma,gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare,glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma,hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma,hyaline carcinoma, hypernephroid carcinoma, infantile embryonalcarcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelialcarcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cellcarcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatouscarcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullarycarcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma,carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma,carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes,nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans,osteoid carcinoma, papillary carcinoma, periportal carcinoma,preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma,renal cell carcinoma of kidney, reserve cell carcinoma, carcinomasarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinomascroti, signet-ring cell carcinoma, carcinoma simplex, small-cellcarcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cellcarcinoma, carcinoma spongiosum, squamous carcinoma, squamous cellcarcinoma, string carcinoma, carcinoma telangiectaticum, carcinomatelangiectodes, transitional cell carcinoma, carcinoma tuberosum,tuberous carcinoma, verrucous carcinoma, or carcinoma villosum.

As used herein, the term “autoimmune disease” refers to a disease orcondition in which a subject's immune system has an aberrant immuneresponse against a substance that does not normally elicit an immuneresponse in a healthy subject. Examples of autoimmune diseases that maybe treated with a compound, pharmaceutical composition, or methoddescribed herein include Acute Disseminated Encephalomyelitis (ADEM),Acute necrotizing hemorrhagic leukoencephalitis, Addison's disease,Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosingspondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome(APS), Autoimmune angioedema, Autoimmune aplastic anemia, Autoimmunedysautonomia, Autoimmune hepatitis, Autoimmune hyperlipidemia,Autoimmune immunodeficiency, Autoimmune inner ear disease (AIED),Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune pancreatitis,Autoimmune retinopathy, Autoimmune thrombocytopenic purpura (ATP),Autoimmune thyroid disease, Autoimmune urticaria, Axonal or neuronalneuropathies, Balo disease, Behcet's disease, Bullous pemphigoid,Cardiomyopathy, Castleman disease, Celiac disease, Chagas disease,Chronic fatigue syndrome, Chronic inflammatory demyelinatingpolyneuropathy (CIDP), Chronic recurrent multifocal ostomyelitis (CRMO),Churg-Strauss syndrome, Cicatricial pemphigoid/benign mucosalpemphigoid, Crohn's disease, Cogans syndrome, Cold agglutinin disease,Congenital heart block, Coxsackie myocarditis, CREST disease, Essentialmixed cryoglobulinemia, Demyelinating neuropathies, Dermatitisherpetiformis, Dermatomyositis, Devic's disease (neuromyelitis optica),Discoid lupus, Dressler's syndrome, Endometriosis, Eosinophilicesophagitis, Eosinophilic fasciitis, Erythema nodosum, Experimentalallergic encephalomyelitis, Evans syndrome, Fibromyalgia, Fibrosingalveolitis, Giant cell arteritis (temporal arteritis), Giant cellmyocarditis, Glomerulonephritis, Goodpasture's syndrome, Granulomatosiswith Polyangiitis (GPA) (formerly called Wegener's Granulomatosis),Graves' disease, Guillain-Barre syndrome, Hashimoto's encephalitis,Hashimoto's thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura,Herpes gestationis, Hypogammaglobulinemia, Idiopathic thrombocytopenicpurpura (ITP), IgA nephropathy, IgG4-related sclerosing disease,Immunoregulatory lipoproteins, Inclusion body myositis, Interstitialcystitis, Juvenile arthritis, Juvenile diabetes (Type 1 diabetes),Juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome,Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneousconjunctivitis, Linear IgA disease (LAD), Lupus (SLE), Lyme disease,chronic, Meniere's disease, Microscopic polyangiitis, Mixed connectivetissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, Multiplesclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neuromyelitis optica(Devic's), Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis,Palindromic rheumatism, PANDAS (Pediatric Autoimmune NeuropsychiatricDisorders Associated with Streptococcus), Paraneoplastic cerebellardegeneration, Paroxysmal nocturnal hemoglobinuria (PNH), Parry Rombergsyndrome, Parsonnage-Turner syndrome, Pars planitis (peripheraluveitis), Pemphigus, Peripheral neuropathy, Perivenousencephalomyelitis, Pernicious anemia, POEMS syndrome, Polyarteritisnodosa, Type I, II, & III autoimmune polyglandular syndromes,Polymyalgia rheumatica, Polymyositis, Postmyocardial infarctionsyndrome, Postpericardiotomy syndrome, Progesterone dermatitis, Primarybiliary cirrhosis, Primary sclerosing cholangitis, Psoriasis, Psoriaticarthritis, Idiopathic pulmonary fibrosis, Pyoderma gangrenosum, Pure redcell aplasia, Raynauds phenomenon, Reactive Arthritis, Reflexsympathetic dystrophy, Reiter's syndrome, Relapsing polychondritis,Restless legs syndrome, Retroperitoneal fibrosis, Rheumatic fever,Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis,Scleroderma, Sjogren's syndrome, Sperm & testicular autoimmunity, Stiffperson syndrome, Subacute bacterial endocarditis (SBE), Susac'ssyndrome, Sympathetic ophthalmia, Takayasu's arteritis, Temporalarteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP),Tolosa-Hunt syndrome, Transverse myelitis, Type 1 diabetes, Ulcerativecolitis, Undifferentiated connective tissue disease (UCTD), Uveitis,Vasculitis, Vesiculobullous dermatosis, Vitiligo, or Wegener'sgranulomatosis (i.e., Granulomatosis with Polyangiitis (GPA).

As used herein, the term “neurodegenerative disease” refers to a diseaseor condition in which the function of a subject's nervous system becomesimpaired. Examples of neurodegenerative diseases that may be treatedwith a compound, pharmaceutical composition, or method described hereininclude Alexander's disease, Alper's disease, Alzheimer's disease,Amyotrophic lateral sclerosis, Ataxia telangiectasia, Batten disease(also known as Spielmeyer-Vogt-Sjogren-Batten disease), Bovinespongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome,Corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporaldementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease,HIV-associated dementia, Kennedy's disease, Krabbe's disease, kuru, Lewybody dementia, Machado-Joseph disease (Spinocerebellar ataxia type 3),Multiple sclerosis, Multiple System Atrophy, Narcolepsy,Neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher Disease,Pick's disease, Primary lateral sclerosis, Prion diseases, Refsum'sdisease, Sandhoffs disease, Schilder's disease, Subacute combineddegeneration of spinal cord secondary to Pernicious Anaemia,Schizophrenia, Spinocerebellar ataxia (multiple types with varyingcharacteristics), Spinal muscular atrophy, Steele-Richardson-Olszewskidisease, or Tabes dorsalis.

As used herein, the term “metabolic disease” refers to a disease orcondition in which a subject's metabolism or metabolic system (e.g.,function of storing or utilizing energy) becomes impaired. Examples ofmetabolic diseases that may be treated with a compound, pharmaceuticalcomposition, or method described herein include diabetes (e.g., type Ior type II), obesity, metabolic syndrome, or a mitochondrial disease(e.g., dysfunction of mitochondria or aberrant mitochondrial function).

As used herein, the term “fungal disease” refers to a disease orcondition associated with a fungus infection of the subject. Examples offungal diseases that may be treated with a compound, pharmaceuticalcomposition, or method described herein include infection with Mucorcircinelloides, zygomycetes, Cryptococcus neoformans, Candida albicans,yeast, and Saccharomyces cerevisiae among others.

As used herein, the term “inflammatory disease” refers to a disease orcondition characterized by aberrant inflammation (e.g. an increasedlevel of inflammation compared to a control such as a healthy person notsuffering from a disease). Examples of inflammatory diseases includetraumatic brain injury, arthritis, rheumatoid arthritis, psoriaticarthritis, juvenile idiopathic arthritis, multiple sclerosis, systemiclupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes,diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto'sencephalitis, Hashimoto's thyroiditis, ankylosing spondylitis,psoriasis, Sjogren's syndrome, vasculitis, glomerulonephritis,auto-immune thyroiditis, Behcet's disease, Crohn's disease, ulcerativecolitis, bullous pemphigoid, sarcoidosis, ichthyosis, Gravesophthalmopathy, inflammatory bowel disease, Addison's disease, Vitiligo,asthma, allergic asthma, acne vulgaris, celiac disease, chronicprostatitis, inflammatory bowel disease, pelvic inflammatory disease,reperfusion injury, sarcoidosis, transplant rejection, interstitialcystitis, atherosclerosis, and atopic dermatitis.

As used herein, the term “cardiovascular disease” refers to a disease orcondition in which the function of a subject's cardiovascular systembecomes impaired. Examples of cardiovascular diseases that may betreated with a compound, pharmaceutical composition, or method describedherein include congestive heart failure; arrhythmogenic syndromes (e.g.,paroxysomal tachycardia, delayed after depolarizations, ventriculartachycardia, sudden tachycardia, exercise-induced arrhythmias, long QTsyndromes, or bidirectional tachycardia); thromboembolic disorders(e.g., arterial cardiovascular thromboembolic disorders, venouscardiovascular thromboembolic disorders, or thromboembolic disorders inthe chambers of the heart); atherosclerosis; restenosis; peripheralarterial disease; coronary bypass grafting surgery; carotid arterydisease; arteritis; myocarditis; cardiovascular inflammation; vascularinflammation; coronary heart disease (CHD); unstable angina (UA);unstable refractory angina; stable angina (SA); chronic stable angina;acute coronary syndrome (ACS); myocardial infarction (first orrecurrent); acute myocardial infarction (AMI); myocardial infarction;non-Q wave myocardial infarction; non-STE myocardial infarction;coronary artery disease; ischemic heart disease; cardiac ischemia;ischemia; ischemic sudden death; transient ischemic attack; stroke;peripheral occlusive arterial disease; venous thrombosis; deep veinthrombosis; thrombophlebitis; arterial embolism; coronary arterialthrombosis; cerebral arterial thrombosis, cerebral embolism; kidneyembolism; pulmonary embolism; thrombosis (e.g., associated withprosthetic valves or other implants, indwelling catheters, stents,cardiopulmonary bypass, hemodialysis); thrombosis (e.g., associated withatherosclerosis, surgery, prolonged immobilization, arterialfibrillation, congenital thrombophilia, cancer, diabetes, hormones, orpregnancy); or cardiac arrhythmias (e.g., supraventricular arrhythmias,atrial arrhythmias, atrial flutter, or atrial fibrillation).

The term “signaling pathway” as used herein refers to a series ofinteractions between cellular and optionally extra-cellular components(e.g. proteins, nucleic acids, small molecules, ions, lipids) thatconveys a change in one component to one or more other components, whichin turn may convey a change to additional components, which isoptionally propagated to other signaling pathway components.

The term “aberrant” as used herein refers to different from normal. Whenused to describe enzymatic activity, aberrant refers to activity that isgreater or less than a normal control or the average of normalnon-diseased control samples. Aberrant activity may refer to an amountof activity that results in a disease, wherein returning the aberrantactivity to a normal or non-disease-associated amount (e.g. byadministering a compound or using a method as described herein), resultsin reduction of the disease or one or more disease symptoms.

The term “amino acid” refers to naturally occurring and synthetic aminoacids, as well as amino acid analogs and amino acid mimetics thatfunction in a manner similar to the naturally occurring amino acids.Naturally occurring amino acids are those encoded by the genetic code,as well as those amino acids that are later modified, e.g.,hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acidanalogs refers to compounds that have the same basic chemical structureas a naturally occurring amino acid, i.e., an a carbon that is bound toa hydrogen, a carboxyl group, an amino group, and an R group, e.g.,homoserine, norleucine, methionine sulfoxide, methionine methylsulfonium. Such analogs have modified R groups (e.g., norleucine) ormodified peptide backbones, but retain the same basic chemical structureas a naturally occurring amino acid. Amino acid mimetics refers tochemical compounds that have a structure that is different from thegeneral chemical structure of an amino acid, but that functions in amanner similar to a naturally occurring amino acid. The terms“non-naturally occurring amino acid” and “unnatural amino acid” refer toamino acid analogs, synthetic amino acids, and amino acid mimetics whichare not found in nature. Examples of amino acid mimetics and polypeptidemimetics include peptoids, D-peptides, and β-peptides. Amino acids maybe modified amino acids (natural or mimetics) including additionalmoieties, for example function, therapeutic, or detectable moieties.Modified amino acids may be modified in the side chain by the additionof additional moieties.

Amino acids may be referred to herein by either their commonly knownthree letter symbols or by the one-letter symbols recommended by theIUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise,may be referred to by their commonly accepted single-letter codes.

Twenty amino acids are commonly found in proteins. Those amino acids canbe grouped into nine classes or groups based on the chemical propertiesof their side chains. Substitution of one amino acid residue for anotherwithin the same class or group is referred to herein as a “conservative”substitution. Conservative amino acid substitutions can frequently bemade in a protein without significantly altering the conformation orfunction of the protein. Substitution of one amino acid residue foranother from a different class or group is referred to herein as a“non-conservative” substitution. In contrast, non-conservative aminoacid substitutions tend to modify conformation and function of aprotein.

Example of Amino Acid Classification

Small/Aliphatic residues: Gly, Ala, Val, Leu, Ile

Cyclic Imino Acid: Pro

Hydroxyl-containing Residues: Ser, Thr

Acidic Residues: Asp, Glu

Amide Residues: Asn, Gln

Basic Residues: Lys, Arg

Imidazole Residue: His

Aromatic Residues: Phe, Tyr, Trp

Sulfur-containing Residues: Met, Cys

In some embodiments, the conservative amino acid substitution comprisessubstituting any of glycine (G), alanine (A), isoleucine (I), valine(V), and leucine (L) for any other of these aliphatic amino acids;serine (S) for threonine (T) and vice versa; aspartic acid (D) forglutamic acid (E) and vice versa; glutamine (Q) for asparagine (N) andvice versa; lysine (K) for arginine (R) and vice versa; phenylalanine(F), tyrosine (Y) and tryptophan (W) for any other of these aromaticamino acids; and methionine (M) for cysteine (C) and vice versa. Othersubstitutions can also be considered conservative, depending on theenvironment of the particular amino acid and its role in thethree-dimensional structure of the protein. For example, glycine (G) andalanine (A) can frequently be interchangeable, as can alanine (A) andvaline (V). Methionine (M), which is relatively hydrophobic, canfrequently be interchanged with leucine and isoleucine, and sometimeswith valine. Lysine (K) and arginine (R) are frequently interchangeablein locations in which the significant feature of the amino acid residueis its charge and the differing pKs of these two amino acid residues arenot significant. Still other changes can be considered “conservative” inparticular environments (see, e.g., BIOCHEMISTRY at pp. 13-15, 2nd ed.Lubert Stryer ed. (Stanford University); Henikoff et al., Proc. Nat'lAcad. Sci. USA (1992) 89:10915-10919; Lei et al., J. Biol. Chem. (1995)270(20):11882-11886).

“Polypeptide,” “peptide,” and “protein” are used herein interchangeablyand mean any peptide-linked chain of amino acids, regardless of lengthor post-translational modification. As noted below, the polypeptidesdescribed herein can be, e.g., wild-type proteins, biologically-activefragments of the wild-type proteins, or variants of the wild-typeproteins or fragments. Variants, in accordance with the disclosure, cancontain amino acid substitutions, deletions, or insertions. Thesubstitutions can be conservative or non-conservative. The terms applyto amino acid polymers in which one or more amino acid residue is anartificial chemical mimetic of a corresponding naturally occurring aminoacid, as well as to naturally occurring amino acid polymers andnon-naturally occurring amino acid polymer. When a polypeptide includesamino acid mimetics or modified amino acids, the monomer may beconnected through bonds that are different from or derivatives ofpeptide links.

Following expression, the proteins can be isolated. The term “purified”or “isolated” as applied to any of the proteins described herein refersto a polypeptide that has been separated or purified from components(e.g., proteins or other naturally-occurring biological or organicmolecules) which naturally accompany it (e.g., other proteins, lipids,and nucleic acid in a cell expressing the proteins). Typically, apolypeptide is purified when it constitutes at least 60 (e.g., at least65, 70, 75, 80, 85, 90, 92, 95, 97, or 99) %, by weight, of the totalprotein in a sample.

An amino acid residue in a protein “corresponds” to a given residue whenit occupies the same essential structural position within the protein asthe given residue. For example, a selected residue in a selected proteincorresponds to a residue when the selected residue occupies the sameessential spatial or other structural relationship as a specifiedresidue relative to the rest of the protein.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the administration of an activeagent to and absorption by a subject and can be included in thecompositions of the present invention without causing a significantadverse toxicological effect on the patient. Non-limiting examples ofpharmaceutically acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors, salt solutions (such as Ringer's solution), alcohols, oils,gelatins, carbohydrates such as lactose, amylose or starch, fatty acidesters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, andthe like. Such preparations can be sterilized and, if desired, mixedwith auxiliary agents such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressure,buffers, coloring, and/or aromatic substances and the like that do notdeleteriously react with the compounds of the invention. One of skill inthe art will recognize that other pharmaceutical excipients are usefulin the present invention.

The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

As used herein, the term “administering” means oral administration,administration as a suppository, topical contact, intravenous,parenteral, intraperitoneal, intramuscular, intralesional, intrathecal,intracranial, intranasal or subcutaneous administration, or theimplantation of a slow-release device, e.g., a mini-osmotic pump, to asubject. Administration is by any route, including parenteral andtransmucosal (e.g., buccal, sublingual, palatal, gingival, nasal,vaginal, rectal, or transdermal). Parenteral administration includes,e.g., intravenous, intramuscular, intra-arteriole, intradermal,subcutaneous, intraperitoneal, intraventricular, and intracranial. Othermodes of delivery include, but are not limited to, the use of liposomalformulations, intravenous infusion, transdermal patches, etc. By“co-administer” it is meant that a composition described herein isadministered at the same time, just prior to, or just after theadministration of one or more additional therapies (e.g. anti-canceragent, anti-autoimmune disease agent, anti-inflammatory disease agent,anti-neurodegenerative disease agent, anti-metabolic disease agent,anti-transplant rejection agent, anti-fungal infection agent, orlongevity agent). The compound of the invention can be administeredalone or can be coadministered to the patient. Coadministration is meantto include simultaneous or sequential administration of the compoundindividually or in combination (more than one compound or agent). Thus,the preparations can also be combined, when desired, with other activesubstances (e.g. to reduce metabolic degradation, to increasedegradation of a prodrug and release of the drug, detectable agent). Thecompositions of the present invention can be delivered by transdermally,by a topical route, formulated as applicator sticks, solutions,suspensions, emulsions, gels, creams, ointments, pastes, jellies,paints, powders, and aerosols. Oral preparations include tablets, pills,powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups,slurries, suspensions, etc., suitable for ingestion by the patient.Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. Liquid formpreparations include solutions, suspensions, and emulsions, for example,water or water/propylene glycol solutions. The compositions of thepresent invention may additionally include components to providesustained release and/or comfort. Such components include high molecularweight, anionic mucomimetic polymers, gelling polysaccharides andfinely-divided drug carrier substrates. These components are discussedin greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and4,861,760. The entire contents of these patents are incorporated hereinby reference in their entirety for all purposes. The compositions of thepresent invention can also be delivered as microspheres for slow releasein the body. For example, microspheres can be administered viaintradermal injection of drug-containing microspheres, which slowlyrelease subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645,1995; as biodegradable and injectable gel formulations (see, e.g., GaoPharm. Res. 12:857-863, 1995); or, as microspheres for oraladministration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674,1997). In another embodiment, the formulations of the compositions ofthe present invention can be delivered by the use of liposomes whichfuse with the cellular membrane or are endocytosed, i.e., by employingreceptor ligands attached to the liposome, that bind to surface membraneprotein receptors of the cell resulting in endocytosis. By usingliposomes, particularly where the liposome surface carries receptorligands specific for target cells, or are otherwise preferentiallydirected to a specific organ, one can focus the delivery of thecompositions of the present invention into the target cells in vivo.(See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn,Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm.46:1576-1587, 1989). The compositions of the present invention can alsobe delivered as nanoparticles.

Pharmaceutical compositions provided by the present invention includecompositions wherein the active ingredient (e.g. compounds describedherein, including embodiments or examples) is contained in atherapeutically effective amount, i.e., in an amount effective toachieve its intended purpose. The actual amount effective for aparticular application will depend, inter alia, on the condition beingtreated. When administered in methods to treat a disease, suchcompositions will contain an amount of active ingredient effective toachieve the desired result, e.g., reducing, eliminating, or slowing theprogression of disease symptoms (e.g. symptoms of cancer, autoimmunedisease, inflammatory disease, metabolic disease, neurodegenerativedisease, fungal infection, or transplant rejection). Determination of atherapeutically effective amount of a compound of the invention is wellwithin the capabilities of those skilled in the art, especially in lightof the detailed disclosure herein.

The dosage and frequency (single or multiple doses) administered to amammal can vary depending upon a variety of factors, for example,whether the mammal suffers from another disease, and its route ofadministration; size, age, sex, health, body weight, body mass index,and diet of the recipient; nature and extent of symptoms of the diseasebeing treated (e.g. symptoms of cancer or neurodegenerative disease),kind of concurrent treatment, complications from the disease beingtreated or other health-related problems. Other therapeutic regimens oragents can be used in conjunction with the methods and compounds ofApplicants' invention. Adjustment and manipulation of establisheddosages (e.g., frequency and duration) are well within the ability ofthose skilled in the art.

For any compound described herein, the therapeutically effective amountcan be initially determined from cell culture assays. Targetconcentrations will be those concentrations of active compound(s) thatare capable of achieving the methods described herein, as measured usingthe methods described herein or known in the art.

As is well known in the art, therapeutically effective amounts for usein humans can also be determined from animal models. For example, a dosefor humans can be formulated to achieve a concentration that has beenfound to be effective in animals. The dosage in humans can be adjustedby monitoring compounds effectiveness and adjusting the dosage upwardsor downwards, as described above. Adjusting the dose to achieve maximalefficacy in humans based on the methods described above and othermethods is well within the capabilities of the ordinarily skilledartisan.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the present invention should be sufficient to effect abeneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side-effects. Determination of the proper dosage for aparticular situation is within the skill of the practitioner. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under circumstances isreached.

Dosage amounts and intervals can be adjusted individually to providelevels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

Utilizing the teachings provided herein, an effective prophylactic ortherapeutic treatment regimen can be planned that does not causesubstantial toxicity and yet is effective to treat the clinical symptomsdemonstrated by the particular patient. This planning should involve thecareful choice of active compound by considering factors such ascompound potency, relative bioavailability, patient body weight,presence and severity of adverse side effects, preferred mode ofadministration and the toxicity profile of the selected agent.

The compounds described herein can be used in combination with oneanother, with other active agents known to be useful in treating cancer,autoimmune disease, inflammatory disease, metabolic disease,neurodegenerative disease, fungal infection, or transplant rejection, orwith adjunctive agents that may not be effective alone, but maycontribute to the efficacy of the active agent. The compounds describedherein can be used in combination with other active agents known to belongevity agents or anti-aging agents.

In some embodiments, co-administration includes administering one activeagent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a secondactive agent. Co-administration includes administering two active agentssimultaneously, approximately simultaneously (e.g., within about 1, 5,10, 15, 20, or 30 minutes of each other), or sequentially in any order.In some embodiments, co-administration can be accomplished byco-formulation, i.e., preparing a single pharmaceutical compositionincluding both active agents. In other embodiments, the active agentscan be formulated separately. In another embodiment, the active and/oradjunctive agents may be linked or conjugated to one another. In someembodiments, the compounds described herein may be combined withtreatments for cancer such as radiation or surgery.

The term “specifically (or significantly or selectively) binds to” whenreferring to a compound described herein binding to a protein or complex(e.g., mTORC1), refers to a binding reaction which is determinative ofthe presence of the protein or complex in the presence of aheterogeneous population of proteins and other biologics. Thus, underdesignated assay conditions, the specified compound binds to aparticular protein (mTOR) or complex (e.g., mTORC1) and does not bind ina significant amount to other proteins or complexes present in thesample (e.g., mTORC2). Specific or significant or selective binding of acompound to mTORC1 and not mTORC2 may be binding to mTORC1 with at least1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10,20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800,900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 10000,20000, 30000, 40000, 50000, 60000, 70000, 80000, 90000, 100000, 100000,200000, 300000, 400000, 500000, 600000, 700000, 800000, 900000, or1000000 fold greater affinity than binding of the identical compound tomTORC2 under identical assay conditions.

The term “mTOR” refers to the protein “mechanistic target of rapamycin(serine/threonine kinase)” or “mammalian target of rapamycin”. The term“mTOR” may refer to the nucleotide sequence or protein sequence of humanmTOR (e.g., Entrez 2475, Uniprot P42345, RefSeq NM_004958, or RefSeqNP_004949) (SEQ ID NO:1). The term “mTOR” includes both the wild-typeform of the nucleotide sequences or proteins as well as any mutantsthereof. In some embodiments, “mTOR” is wild-type mTOR. In someembodiments, “mTOR” is one or more mutant forms. The term “mTOR” XYZrefers to a nucleotide sequence or protein of a mutant mTOR wherein theY numbered amino acid of mTOR that normally has an X amino acid in thewildtype, instead has a Z amino acid in the mutant. In embodiments, anmTOR is the human mTOR. In embodiments, the mTOR has the nucleotidesequence corresponding to reference number GI:206725550 (SEQ ID NO:2).In embodiments, the mTOR has the nucleotide sequence corresponding toRefSeq NM_004958.3 (SEQ ID NO:2). In embodiments, the mTOR has theprotein sequence corresponding to reference number GI:4826730 (SEQ IDNO:1). In embodiments, the mTOR has the protein sequence correspondingto RefSeq NP_004949.1 (SEQ ID NO:1). In embodiments, the mTOR has thefollowing amino acid sequence:

MLGTGPAAATTAATTSSNVSVLQQFASGLKSRNEETRAKAAKELQHYVTMELREMSQEESTRFYDQLNHHIFELVSSSDANERKGGILAIASLIGVEGGNATRIGRFANYLRNLLPSNDPVVMEMASKAIGRLAMAGDTFTAEYVEFEVKRALEWLGADRNEGRRHAAVLVLRELAISVPTFFFQQVQPFFDNIFVAVWMPKQAIREGAVAALRACLILTTQREPKEMQKPQWYRHTFEEAEKGFDETLAKEKGMNRDDRIHGALLILNELVRISSMEGERLREEMEEITQQQLVHDKYCKDLMGFGTKPRHITPFTSFQAVQPQQSNALVGLLGYSSHQGLMGFGTSPSPAKSTLVESRCCRDLMEEKFDQVCONVLKCRNSKNSLIQMTILNLLPRLAAFRPSAFTDTQYLQDTMNHVLSCVKKEKERTAAFQALGLLSVAVRSEFKVYLPRVLDIIRAALPPKDFAHKRQKAMQVDATVFTCISMLARAMGPGIQQDIKELLEPMLAVGLSPALTAVLYDLSRQIPQLKKDIQDGLLKMLSLVLMHKPLRHPGMPKGLAHQLASPGLTTLPEASDVGSITLALRTLGSFEFEGHSLTQFVRHCADHFLNSEHKEIRMEAARTCSRLLTPSIHLISGHAHVVSQTAVQVVADVLSKLLVVGITDPDPDIRYCVLASLDERFDAHLAQAENLQALFVALNDQVFEIRELAICTVGRLSSMNPAFVMPFLRKMLIQILTELEHSGIGRIKEQSARMLGHLVSNAPRLIRPYMEPILKALILKLKDPDPDPNPGVINNVLATIGELAQVSGLEMRKWVDELFIIIMDMLQDSSLLAKRQVALWTLGQLVASTGYVVEPYRKYPILLEVLLNFLKTEQNQGTRREAIRVLGLLGALDPYKHKVNIGMIDQSRDASAVSLSESKSSQDSSDYSTSEMLVNMGNLPLDEFYPAVSMVALMRIFRDQSLSHHHTMVVQAITFIFKSLGLKCVQFLPQVMPTFLNVIRVCDGAIREFLFQQLGMLVSFVKSHIRPYMDEIVTLMREFWVMNTSIQSTIILLIEQIVVALGGEFKLYLPQLIPHMLRVFMHDNSPGRIVSIKLLAAIQLFGANLDDYLHLLLPPIVKLFDAPEAPLPSRKAALETVDRLTESLDFTDYASRIIHPIVRTLDQSPELRSTAMDTLSSLVFQLGKKYQIFIPMVNKVLVRHRINHQRYDVLICRIVKGYTLADEEEDPLIYQHRMLRSGQGDALASGPVETGPMKKLHVSTINLQKAWGAARRVSKDDWLEWLRRLSLELLKDSSSPSLRSCWALAQAYNPMARDLFNAAFVSCWSELNEDQQDELIRSIELALTSQDIAEVTQTLLNLAEFMEHSDKGPLPLRDDNGIVLLGERAAKCRAYAKALHYKELEFQKGPTPAILESLISINNKLQQPEAAAGVLEYAMKHFGELEIQATWYEKLHEWEDALVAYDKKMDTNKDDPELMLGRMRCLEALGEWGQLHQQCCEKWILVNDETQAKMARMAAAAAWGLGQWDSMEEYTCMIPRDTHDGAFYRAVLALHQDLFSLAQQCIDKARDLLDAELTAMAGESYSRAYGAMVSCHMLSELEEVIQYKLVPERREIIRQIWWERLQGCQRIVEDWQKILMVRSLVVSPHEDMRTWLKYASLCGKSGRLALAHKTLVLLLGVDPSRQLDHPLPTVHPQVTYAYMKNMWKSARKIDAFQHMQHFVQTMQQQAQHAIATEDQQHKQELHKLMARCFLKLGEWQLNLQGINESTIPKVLQYYSAATEHDRSWYKAWHAWAVMNFEAVLHYKHQNQARDEKKKLRHASGANITNATTAATTAATATTTASTEGSNSESEAESTENSPTPSPLQKKVTEDLSKTLLMYTVPAVQGFFRSISLSRGNNLQDTLRVLTLWFDYGHWPDVNEALVEGVKAIQIDTWLQVIPQLIARIDTPRPLVGRLIHQLLTDIGRYHPQALIYPLTVASKSTTTARHNAANKILKNMCEHSNTLVQQAMMVSEELIRVAILWHEMWHEGLEEASRLYFGERNVKGMFEVLEPLHAMMERGPQTLKETSFNQAYGRDLMEAQEWCRKYMKSGNVKDLTQAWDLYYHVFRRISKQLPQLTSLELQYVSPKLLMCRDLELAVPGTYDPNQPIIRIQSIAPSLQVITSKQRPRKLTLMGSNGHEFVFLLKGHEDLRQDERVMQLFGLVNTLLANDPTSLRKNLSIQRYAVIPLSTNSGLIGWVPHCDTLHALIRDYREKKKILLNIEHRIMLRMAPDYDHLTLMQKVEVFEHAVNNTAGDDLAKLLWLKSPSSEVWFDRRTNYTRSLAVMSMVGYILGLGDRHPSNLMLDRLSGKILHIDFGDCFEVAMTREKFPEKIPFRLTRMLTNAMEVTGLDGNYRITCHTVMEVLREHKDSVMAVLEAFVYDPLLNWRLMDINTKGNKRSRTRIDSYSAGQSVEILDGVELGEPAHKKTGTTVPESIHSFIGDGLVKPEALNKKAIQIINRVRDKLTGRDFSHDDILDVPTQVELLIKQATSHENLCQCYIGWCPF W

In embodiments, the mTOR is a mutant mTOR. In embodiments, the mutantmTOR is associated with a disease that is not associated with wildtypemTOR. In embodiments, the mTOR includes at least one amino acid mutation(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations) compared tothe sequence above.

The term “mTORC1” refers to the protein complex including mTOR andRaptor (regulatory-associated protein of mTOR). mTORC1 may also includeMLST8 (mammalian lethal with SEC13 protein 8), PRAS40, and/or DEPTOR.mTORC1 may function as a nutrient/energy/redox sensor and regulator ofprotein synthesis. The term “mTORC1 pathway” or “mTORC1 signaltransduction pathway” refers to a cellular pathway including mTORC1. AnmTORC1 pathway includes the pathway components upstream and downstreamfrom mTORC1. An mTORC1 pathway is a signaling pathway that is modulatedby modulation of mTORC1 activity. In embodiments, an mTORC1 pathway is asignaling pathway that is modulated by modulation of mTORC1 activity butnot by modulation of mTORC2 activity. In embodiments, an mTORC1 pathwayis a signaling pathway that is modulated to a greater extent bymodulation of mTORC1 activity than by modulation of mTORC2 activity.

The term “mTORC2” refers to the protein complex including mTOR andRICTOR (rapamycin-insensitive companion of mTOR). mTORC2 may alsoinclude GβL, mSIN1 (mammalian stress-activated protein kinaseinteracting protein 1), Protor 1/2, DEPTOR, TTI1, and/or TEL2. mTORC2may regulate cellular metabolism and the cytoskeleton. The term “mTORC2pathway” or “mTORC2 signal transduction pathway” refers to a cellularpathway including mTORC2. An mTORC2 pathway includes the pathwaycomponents upstream and downstream from mTORC2. An mTORC2 pathway is asignaling pathway that is modulated by modulation of mTORC2 activity. Inembodiments, an mTORC2 pathway is a signaling pathway that is modulatedby modulation of mTORC2 activity but not by modulation of mTORC1activity. In embodiments, an mTORC2 pathway is a signaling pathway thatis modulated to a greater extent by modulation of mTORC2 activity thanby modulation of mTORC1 activity.

The term “rapamycin” or “sirolimus” refers to a macrolide produced bythe bacteria Streptomyces hygroscopicus. Rapamycin may prevent theactivation of T cells and B cells. Rapamycin has the IUPAC name(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]-oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone.Rapamycin has the CAS number 53123-88-9. Rapamycin may be producedsynthetically (e.g., by chemical synthesis) or through use of aproduction method that does not include use of Streptomyceshygroscopicus.

“Analog” is used in accordance with its plain ordinary meaning withinChemistry and Biology and refers to a chemical compound that isstructurally similar to another compound (i.e., a so-called “reference”compound) but differs in composition, e.g., in the replacement of oneatom by an atom of a different element, or in the presence of aparticular functional group, or the replacement of one functional groupby another functional group, or the absolute stereochemistry of one ormore chiral centers of the reference compound, including isomersthereof. Accordingly, an analog is a compound that is similar orcomparable in function and appearance but not in structure or origin toa reference compound.

The term “rapaymcin analog” or “rapalog” refer to analogs or derivatives(e.g., prodrugs) of rapamycin. Examples of rapamycin analogs include,but are not limited to, deforolimus (AP23573, MK-8669, ridaforolimus),temsirolimus (CCI-779), ABT478, and everolimus (RAD001). In embodiments,rapamycin analogs include esters, ethers, amides, carbonates,carbamates, sulfonates, oximes, hydrazones, or hydroxyamines ofrapamycin. In embodiments, rapamycin analogs include rapamycins in whichfunctional groups on rapamycin have been modified, (e.g., throughreduction or oxidation, replacement with a nucleophile). In embodiments,rapamycin analogs include a metabolite of rapamycin (e.g., adesmethylrapamycin derivative or a linear rapamycin (e.g.,secorapamycin, as described in U.S. Pat. No. 5,252,579). In embodiments,rapamycin analogs include O-desmethylrapamycin, desmethylrapamycin, ordesmethoxyrapamycin (for example, as described in WO 2006/095185, U.S.Pat. No. 6,358,969). In embodiments, rapamycin analogs include esterderivatives or ether derivatives of rapamycin, including alkyl esters(U.S. Pat. No. 4,316,885); aminoalkyl esters (U.S. Pat. No. 4,650,803);fluorinated esters (U.S. Pat. No. 5,100,883); amide esters (U.S. Pat.No. 5,118,677); carbamate esters (U.S. Pat. Nos. 5,118,678; 5,411,967;5,480,989; 5,480,988; 5,489,680); amino carbamate esters (U.S. Pat. No.5,463,048); silyl ethers (U.S. Pat. No. 5,120,842); aminoesters (U.S.Pat. No. 5,130,307); acetals; aminodiesters (U.S. Pat. No. 5,162,333);sulfonate and sulfate esters (U.S. Pat. No. 5,177,203); esters (U.S.Pat. No. 5,221,670); alkoxyesters (U.S. Pat. No. 5,233,036); O-aryl,-alkyl, -alkenyl, and -alkynyl ethers (U.S. Pat. No. 5,258,389);carbonate esters (U.S. Pat. No. 5,260,300); arylcarbonyl andalkoxycarbonyl carbamates (U.S. Pat. No. 5,262,423); carbamates (U.S.Pat. No. 5,302,584); hydroxyesters (U.S. Pat. No. 5,362,718); hinderedesters (U.S. Pat. No. 5,385,908); heterocyclic esters (U.S. Pat. No.5,385,909); gem-disubstituted esters (U.S. Pat. No. 5,385,910); aminoalkanoic esters (U.S. Pat. No. 5,389,639); phosphorylcarbamate esters(U.S. Pat. No. 5,391,730); hindered N-oxide esters (U.S. Pat. No.5,491,231); biotin esters (U.S. Pat. No. 5,504,091); O-alkyl ethers(U.S. Pat. No. 5,665,772); and PEG esters (U.S. Pat. No. 5,780,462); allof rapamycin. In embodiments, rapamycin analogs include ester, oxime,hydrazone, ether, or hydroxylamine derivatives of rapamycin, includingthose described in U.S. Pat. Nos. 5,256,790, 5,373,014, 5,378,836,5,023,264, 5,563,145, and 5,023,263. In embodiments, rapamycin analogsinclude rapamycin 42-ester with3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid (U.S. Pat. No.5,362,718), 42-Q-(2-hydroxy)ethyl rapamycin (U.S. Pat. No. 5,665,772),and 42-epi-tetrazolyl rapamycin, or those described in U.S. Pat. Nos.3,929,992, 5,362,718, and 6,277,983 (e.g., position 42 corresponding toposition 40 shown in Example tables). In embodiments, rapamycin analogsinclude a substituted rapamycin e.g. a 40-O-substituted rapamycin e.g.as described in U.S. Pat. No. 5,258,389, WO 94/09010, WO 92/05179, U.S.Pat. Nos. 5,118,677, 5,118,678, 5,100,883, 5,151,413, 5,120,842, WO93/11130, WO 94/02136, WO 94/02485 or WO 95/14023. In embodiments,rapamycin analogs include a 16-O-substituted rapamycin e.g. as disclosedin WO 94/02136, WO 95/16691 or WO 96/41807. In embodiments, rapamycinanalogs include a 32-hydrogenated rapamycin e.g. as described in WO96/41807 or U.S. Pat. No. 5,256,790. In embodiments, rapamycin analogsinclude 32-deoxorapamycin, 16-pent-2-ynyloxy-32-deoxorapamycin,16-pent-2-ynyloxy-32(S)-dihydro-rapamycin,16-pent-2-ynyloxy-32(S)-dihydro-40-O-(2-hydroxyethyl)-rapamycin or40-O-(2-hydroxyethyl)-rapamycin. In embodiments, rapamycin analogsinclude 40-O-(2-hydroxyethyl)-rapamycin,40-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]-rapamycin (alsocalled CCI779), 40-epi-(tetrazolyl)-rapamycin (also called ABT578),32-deoxorapamycin, 16-pent-2-ynyloxy-32(S)-dihydro rapamycin, orTAFA-93. The publications, patents, and applications described above areincorporated by reference in their entireties for all purposes.

The term “active site mTOR inhibitor” refers to a compound that inhibitsthe activity of mTOR (e.g., kinase activity) and binds to the activesite of mTOR (e.g., the ATP binding site, overlapping with the ATPbinding site, blocking access by ATP to the ATP binding site of mTOR).Examples of active site mTOR inhibitors include, but are not limited to,INK128, PP242, PP121, MLN0128, AZD8055, AZD2014, NVP-BEZ235, BGT226,SF1126, Torin 1, Torin 2, WYE 687, WYE 687 salt (e.g., hydrochloride),PF04691502, PI-103, CC-223, OSI-027, XL388, KU-0063794, GDC-0349, andPKI-587. In embodiments, an active site mTOR inhibitor is an asTORi.

The term “FKBP” refers to the protein Peptidyl-prolyl cis-transisomerase. For non-limiting examples of FKBP, see Cell Mol Life Sci.2013 September;70(18):3243-75. In embodiments, “FKBP” refers to“FKBP-12” or “FKBP 12” or “FKBP1A”. In embodiments, “FKBP” refers to thehuman protein. Included in the term “FKBP” is the wildtype and mutantforms of the protein. In embodiments, “FKBP” refers to the wildtypehuman protein. In embodiments, “FKBP” refers to the wildtype humannucleic acid. In embodiments, the FKBP is a mutant FKBP. In embodiments,the mutant FKBP is associated with a disease that is not associated withwildtype FKBP. In embodiments, the FKBP includes at least one amino acidmutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations)compared to wildtype FKBP.

The term “FKBP-12” or “FKBP 12” or “FKBP1A” refers to the protein“Peptidyl-prolyl cis-trans isomerase FKBP1A”. In embodiments, ““FKBP-12”or “FKBP 12” or “FKBP1A” refers to the human protein. Included in theterm “FKBP-12” or “FKBP 12” or “FKBP1A” are the wildtype and mutantforms of the protein. In embodiments, “FKBP-12” or “FKBP 12” or “FKBP1A”refers to the protein associated with Entrez Gene 2280, OMIM 186945,UniProt P62942, and/or RefSeq (protein) NP_000792 (SEQ ID NO:3). Inembodiments, the reference numbers immediately above refer to theprotein, and associated nucleic acids, known as of the date of filing ofthis application. In embodiments, “FKBP-12” or “FKBP 12” or “FKBP1A”refers to the wildtype human protein. In embodiments, “FKBP-12” or “FKBP12” or “FKBP1A” refers to the wildtype human nucleic acid. Inembodiments, the FKBP-12 is a mutant FKBP-12. In embodiments, the mutantFKBP-12 is associated with a disease that is not associated withwildtype FKBP-12. In embodiments, the FKBP-12 includes at least oneamino acid mutation (e.g., 1, 2, 3, 4, 5,6,7,8,9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30mutations) compared to wildtype FKBP-12. In embodiments, the FKBP-12 hasthe protein sequence corresponding to reference number GI:206725550. Inembodiments, the FKBP-12 has the protein sequence corresponding toRefSeq NP_000792.1 (SEQ ID NO:3).

The term “4E-BP1” or “4EBP1” or “EIF4EBP1” refers to the protein“Eukaryotic translation initiation factor 4E-binding protein 1”. Inembodiments, “4E-BP1” or “4EBP1” or “EIF4EBP1” refers to the humanprotein. Included in the term “4E-BP1” or “4EBP1” or “EIF4EBP1” are thewildtype and mutant forms of the protein. In embodiments, “4E-BP1” or“4EBP1” or “EIF4EBP1” refers to the protein associated with Entrez Gene1978, OMIM 602223, UniProt Q13541, and/or RefSeq (protein) NP_004086(SEQ ID NO:4). In embodiments, the reference numbers immediately aboverefer to the protein, and associated nucleic acids, known as of the dateof filing of this application. In embodiments, ““4E-BP1” or “4EBP1” or“EIF4EBP1” refers to the wildtype human protein. In embodiments,“4E-BP1” or “4EBP1” or “EIF4EBP1” refers to the wildtype human nucleicacid. In embodiments, the 4EBP1 is a mutant 4EBP1. In embodiments, themutant 4EBP1 is associated with a disease that is not associated withwildtype 4EBP1. In embodiments, the 4EBP1 includes at least one aminoacid mutation (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mutations)compared to wildtype 4EBP1. In embodiments, the 4EBP1 has the proteinsequence corresponding to reference number GI:4758258. In embodiments,the 4EBP1 has the protein sequence corresponding to RefSeq NP_004086.1(SEQ ID NO:4).

The term “Akt” refers to the serine/threonine specific protein kinaseinvolved in cellular processes such as glucose metabolism, apoptosis,proliferation, and other functions, also known as “protein kinase B”(PKB) or “Akt1”. In embodiments, “Akt” or “Akt1” or “PKB” refers to thehuman protein. Included in the term “Akt” or “Akt1” or “PKB” are thewildtype and mutant forms of the protein. In embodiments, “Akt” or“Akt1” or “PKB” refers to the protein associated with Entrez Gene 207,OMIM 164730, UniProt P31749, and/or RefSeq (protein) NP_005154 (SEQ IDNO:5). In embodiments, the reference numbers immediately above refer tothe protein, and associated nucleic acids, known as of the date offiling of this application. In embodiments, “Akt” or “Akt1” or “PKB”refers to the wildtype human protein. In embodiments, “Akt” or “Akt1” or“PKB” refers to the wildtype human nucleic acid. In embodiments, the Aktis a mutant Akt. In embodiments, the mutant Akt is associated with adisease that is not associated with wildtype Akt. In embodiments, theAkt includes at least one amino acid mutation (e.g., 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, or 30 mutations) compared to wildtype Akt. Inembodiments, the Akt has the protein sequence corresponding to referencenumber GI:62241011. In embodiments, the Akt has the protein sequencecorresponding to RefSeq NP_005154.2 (SEQ ID NO:5).

The term “longevity” is used in accordance with its plain ordinarymeaning and refers to a long life or the extension of life expectancybeyond an average life expectancy. A “longevity agent” is an agent(e.g., composition as described herein) capable of extending the lifeexpectancy of a subject in comparison to the life expectancy of thesubject in the absence of the agent (Lamming, D. W., et al. (2012).Science (New York, N.Y.), 335(6076), 1638-1643, McCormick, M. A., et al.(2011). Philosophical Transactions of the Royal Society B: BiologicalSciences, 366(1561)). A longevity agent may be capable of inducing oneor more anti-aging effects in a subject wherein an aging effect is acondition or symptom of aging normally found in a similar subject.

As used herein, the term “about” means a range of values including thespecified value, which a person of ordinary skill in the art wouldconsider reasonably similar to the specified value. In embodiments,about means within a standard deviation using measurements generallyacceptable in the art. In embodiments, about means a range extending to+/−10% of the specified value. In embodiments, about means the specifiedvalue.

A. Compounds and Compositions

In an aspect is provided a compound including a monovalent active sitemTOR inhibitor covalently bound to a monovalent rapamycin or amonovalent rapamycin analog.

In embodiments, a divalent linker binds the monovalent active site mTORinhibitor (active site mTOR inhibitor moiety) to the monovalentrapamycin (rapamycin moiety) or the monovalent rapamycin analog(rapamycin analog moiety). The divalent linker may be bonded torapamycin or a rapamycin analog at a position capable of being modifiedto include a linker. For example, a linker may be bonded to rapamycin ora rapamycin analog at position 10, 16, 27, 28, 39, or 40, among others(as indicated in figure immediately below). In embodiments, a linker isbonded to position 10 of rapamycin or a rapamycin analog. Inembodiments, a linker is bonded to position 16 of rapamycin or arapamycin analog. In embodiments, a linker is bonded to position 27 ofrapamycin or a rapamycin analog. In embodiments, a linker is bonded toposition 28 of rapamycin or a rapamycin analog. In embodiments, a linkeris bonded to position 39 of rapamycin or a rapamycin analog. Inembodiments, a linker is bonded to position 40 of rapamycin or arapamycin analog.

In embodiments, the divalent linker is at least about or about 5 Å inlength (e.g., at least about or about 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6,5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0,7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4,8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8,9.9, 10.0, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97,98, 99, or 100 Å in length). In embodiments, the divalent linker is atleast about or about the length of 5 methylene groups (e.g., 5, 6,7,8,9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, or 50 methylene groups). In embodiments, the divalentlinker is at least about or about the length of 11 methylene groups(e.g., at least about or about 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38,39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 methylene groups). Inembodiments, the divalent linker is at least about or about the lengthof 27 methylene groups (e.g., 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 methylenegroups). In embodiments, the divalent linker is from about 5 to 54 Å inlength. In embodiments, the divalent linker is from about 6 to 54 Å inlength. In embodiments, the divalent linker is from about 7 to 54 Å inlength. In embodiments, the divalent linker is from about 9 to 54 Å inlength. In embodiments, the divalent linker is from about 11 to 54 Å inlength. In embodiments, the divalent linker is from about 13 to 54 Å inlength. In embodiments, the divalent linker is from about 15 to 54 Å inlength. In embodiments, the divalent linker is from about 20 to 54 Å inlength. In embodiments, the divalent linker is from about 24 to 54 Å inlength. In embodiments, the divalent linker is from about 28 to 54 Å inlength. In embodiments, the divalent linker is from about 5 to 50 Å inlength. In embodiments, the divalent linker is from about 5 to 46 Å inlength. In embodiments, the divalent linker is from about 5 to 42 Å inlength. In embodiments, the divalent linker is from about 5 to 38 Å inlength. In embodiments, the divalent linker is from about 5 to 34 Å inlength. In embodiments, the divalent linker is from about 5 to 30 Å inlength. In embodiments, the divalent linker is from about 5 to 26 Å inlength. In embodiments, the divalent linker is from about 5 to 22 Å inlength. In embodiments, the divalent linker is from about 5 to 39 Å inlength. In embodiments, the divalent linker is from about 7 to 37 Å inlength. In embodiments, the divalent linker is from about 9 to 35 Å inlength. In embodiments, the divalent linker is from about 11 to 33 Å inlength. In embodiments, the divalent linker is from about 13 to 31 Å inlength. In embodiments, the divalent linker is from about 15 to 29 Å inlength. In embodiments, the divalent linker is from about 15 to 25 Å inlength. In embodiments, the divalent linker is from about 15 to 23 Å inlength. In embodiments, the divalent linker is at least about or about32 Å in length (e.g., at least about or about 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,92, 93, 94, 95, 96, 97, 98, 99, or 100 Å in length). In embodiments, thedivalent linker is at least about or about the length of 27 methylenegroups. In embodiments, the divalent linker is from about 32 to 54 Å inlength. In embodiments, the divalent linker is from about 33 to 53 Å inlength. In embodiments, the divalent linker is from about 34 to 52 Å inlength. In embodiments, the divalent linker is from about 35 to 51 Å inlength. In embodiments, the divalent linker is from about 36 to 50 Å inlength. In embodiments, the divalent linker is from about 37 to 49 Å inlength. In embodiments, the divalent linker is from about 38 to 48 Å inlength. In embodiments, the divalent linker is from about 39 to 47 Å inlength. In embodiments, the divalent linker is from about 40 to 46 Å inlength. In embodiments, the divalent linker is from about 41 to 45 Å inlength. In embodiments, the divalent linker is from about 42 to 44 Å inlength. In embodiments, the divalent linker is from about 32 to 52 Å inlength. In embodiments, the divalent linker is from about 32 to 50 Å inlength. In embodiments, the divalent linker is from about 32 to 48 Å inlength. In embodiments, the divalent linker is from about 32 to 46 Å inlength. In embodiments, the divalent linker is from about 32 to 44 Å inlength. In embodiments, the divalent linker is from about 32 to 42 Å inlength. In embodiments, the divalent linker is from about 32 to 40 Å inlength. In embodiments, the divalent linker is from about 32 to 38 Å inlength. In embodiments, the divalent linker is from about 32 to 36 Å inlength. In embodiments, the divalent linker is from about 34 to 54 Å inlength. In embodiments, the divalent linker is from about 36 to 54 Å inlength. In embodiments, the divalent linker is from about 38 to 54 Å inlength. In embodiments, the divalent linker is from about 40 to 54 Å inlength. In embodiments, the divalent linker is from about 42 to 54 Å inlength. In embodiments, the divalent linker is from about 44 to 54 Å inlength. In embodiments, the divalent linker is from about 46 to 54 Å inlength. In embodiments, the divalent linker is from about 48 to 54 Å inlength. In embodiments, the divalent linker is from about 50 to 54 Å inlength.

The specified length of a linker is the through space distance betweenthe ends of the linker (i.e., the ends or termini that are connected tothe two parts of the molecule connected by the linker) wherein thelength of the linker is measured when the linker is fully extended andwherein the linker termini are the furthest apart they may naturallyexist in solution (i.e., the longest distance between the ends of thelinker wherein the linker adopts allowable conformations, bond lengths,and bond angles following the principles of Chemistry), (e.g., withoutadopting non-natural bond lengths, non-allowed or non-preferred bondangles, or high energy non-preferred or non-natural interactions ofdifferent components of the linker). In embodiments, the linker lengthis measured when included in a compound as described herein (e.g.,aspect, embodiment, example, figures, table, claim). It will beunderstood that a linker may adopt a through space distance (e.g., insolution, when bound to mTORC1, when bound to mTOR) that is less thanthe fully extended conformation used to define the linker length.

In embodiments, the linker is a hydrolysable linker (e.g., in solution).In embodiments, the linker is a non-hydrolysable linker (e.g., insolution). In embodiments, the linker may be cleaved by an enzyme (e.g.,hydrolase, protease, cytochrome). In embodiments, the linker is notcleavable by an enzyme (e.g., under normal cellular conditions). Inembodiments, the linker is a polyethylene glycol linker. In embodiments,the linker is hydrophilic. In embodiments, the linker is hydrophobic. Inembodiments, the linker includes a disulfide bond. In embodiments, thelinker includes a hydrazone bond. In embodiments, the linker includes anester. In embodiments, the linker includes a sulfonyl. In embodiments,the linker includes a thioether. In embodiments, the linker includes aphosphinate. In embodiments, the linker includes an alkyloxime bond. Inembodiments, the linker includes one or more amino acids. Inembodiments, the linker consists of amino acids. In embodiments, thelinker includes an amino acid analog. In embodiments, the linkerincludes an amino acid mimetic. In embodiments, the linker is a linkerknown in the art for use in linking antibodies to agents (e.g., antibodydrug conjugates). In embodiments, the linker is a linker as described inBioconjugate Techniques (Second Edition) by Greg T. Hermanson (2008),which is herein incorporated by referenced in its entirety for allpurposes. In embodiments, the linker is a linker as described in FlygareJ A, Pillow T H, Aristoff P., Antibody-drug conjugates for the treatmentof cancer. Chemical Biology and Drug Design. 2013 January;81(1):113-21,which is herein incorporated by referenced in its entirety for allpurposes. In embodiments, the linker is a linker as described inDrachman J G, Senter P D., Antibody-drug conjugates: the chemistrybehind empowering antibodies to fight cancer. Hematology Am Soc HematolEduc Program. 2013; 2013:306-10, which is herein incorporated byreferenced in its entirety for all purposes.

In embodiments, the compound includes a divalent linker covalently boundto the monovalent active site mTOR inhibitor and the monovalentrapamycin or monovalent rapamycin analog. In embodiments, the compoundincludes a divalent linker covalently bound directly to the monovalentactive site mTOR inhibitor and directly to the monovalent rapamycin ormonovalent rapamycin analog.

In embodiments, the active site mTOR inhibitor is an asTORi. Inembodiments, the active site mTOR inhibitor is INK128. In embodiments,the active site mTOR inhibitor is PP242. In embodiments, the active sitemTOR inhibitor is PP121. In embodiments, the active site mTOR inhibitoris MLN0128. In embodiments, the active site mTOR inhibitor is AZD8055.In embodiments, the active site mTOR inhibitor is AZD2014. Inembodiments, the active site mTOR inhibitor is NVP-BEZ235. Inembodiments, the active site mTOR inhibitor is BGT226. In embodiments,the active site mTOR inhibitor is SF1126. In embodiments, the activesite mTOR inhibitor is Torin 1. In embodiments, the active site mTORinhibitor is Torin 2. In embodiments, the active site mTOR inhibitor isWYE 687. In embodiments, the active site mTOR inhibitor is WYE 687 salt(e.g., hydrochloride). In embodiments, the active site mTOR inhibitor isPF04691502. In embodiments, the active site mTOR inhibitor is PI-103,CC-223. In embodiments, the active site mTOR inhibitor is OSI-027,XL388. In embodiments, the active site mTOR inhibitor is KU-0063794. Inembodiments, the active site mTOR inhibitor is GDC-0349. In embodiments,the active site mTOR inhibitor is PKI-587. When included in thecompounds described herein, an active site mTOR inhibitor describedabove and elsewhere herein will be understood to be a monovalent form ofthe described active site mTOR inhibitor.

In embodiments, the compound has the formula:

wherein L¹ is as described herein and may be bonded to any atom in thering (L¹ is a floating substituent) and R¹⁰⁰ is a monovalent active sitemTOR inhibitor.

In embodiments, the compound has the formula:

wherein L¹ is as described herein and may be bonded to any atom in thering (L¹ is a floating substituent) and R¹⁰⁰ is a monovalent active sitemTOR inhibitor.

In embodiments, the compound has the formula:

wherein L¹ is as described herein and may be bonded to any atom in thering (L¹ is a floating substituent) and R¹⁰⁰ is a monovalent active sitemTOR inhibitor.

In embodiments, the compound has the formula:

wherein L¹ is as described herein and may be bonded to any atom in thering (L¹ is a floating substituent) and R¹⁰⁰ is a monovalent active sitemTOR inhibitor.

R¹⁰⁰ is a monovalent active site mTOR inhibitor. In embodiments, R¹⁰⁰ is

wherein W¹, W², W³, W⁴, and R³ are as described herein. In embodiments,R¹⁰⁰ is

wherein W¹, W², W³, W⁴, and R³ are as described herein. In embodiments,R¹⁰⁰ is

wherein R³ and R¹² are as described herein. In embodiments, R¹⁰⁰ is

wherein R³, R¹¹, and R¹² are as described herein. In embodiments, R¹⁰⁰is

wherein R³ is as described herein. In embodiments, R¹⁰⁰ is

wherein R³ and R¹¹ are as described herein. In embodiments, R¹⁰⁰ is

wherein R³, R¹, and R¹² are as described herein. In embodiments, R¹⁰⁰ is

wherein R³ and R¹² are as described herein.

In embodiments, the compound has the formula:

wherein W¹, W², W³, W⁴, L¹, Y, and R³ are as described herein.

In embodiments, the compound has the formula:

wherein L¹, Y, and R¹⁰⁰ are as described herein.

In embodiments, the compound has the formula:

wherein L¹, Y, R³, and R¹¹ are as described herein.

In embodiments, the compound has the formula:

wherein L¹, Y, R³, W¹, and R¹² are as described herein.

In embodiments, the compound has the formula:

wherein L¹, Y, R³, W¹, and W⁴ are as described herein.

L¹ is a divalent linker as described herein. W¹ is N or CR¹¹. W² is Nand W³ is C or, alternatively, W² is C and W³ is N. W⁴ is N or CR¹². Yis O or NR¹³. R³ is hydrogen, oxo, halogen, —CX₃, —CN, —SO₂Cl,—SO_(n)R¹⁰, —SO_(v)NR⁷RB, —NHNH₂, —ONR⁷R⁸, —NHC═(O)NHNH₂, —NHC═(O)NR⁷R⁸,—N(O)_(m), —NR⁷RB, —C(O)R⁹, —C(O)—OR⁹, —C(O)NR⁷R⁸, —OR¹⁰, —NR⁷SO₂R¹⁰,—NR⁷C═(O)R⁹, —NR⁷C(O)OR⁹, —NR⁷OR⁹, —OCX₃, —OCHX₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², and R¹³ areindependently hydrogen, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCHF₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R⁷ and R⁸ substituents bondedto the same nitrogen atom may optionally be joined to form a substitutedor unsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl. The variables m and v are independently 1 or 2. The variablen is independently an integer from 0 to 4. The variable X isindependently —Cl, —Br, —I, or —F. In embodiments, L¹ is a divalentlinker including one or more amino acids. In embodiments, L¹ is adivalent linker consisting of amino acids (i.e. a peptidyl linker). Inembodiments, L¹ is a divalent linker (e.g. a peptidyl linker) includingan amino acid analog. In embodiments, L¹ is a divalent linker (e.g. apeptidyl linker) including an amino acid mimetic. In embodiments, L¹ isa divalent linker consisting of amino acid analogs (also referred toherein as a peptidyl analog linker). In embodiments, L¹ is a divalentlinker consisting of amino acid mimetics (also referred to herein as apeptidyl mimetic linker).

In embodiments, W¹ is N. In embodiments, W¹ is CR¹¹. In embodiments, W²is N and W³ is C. In embodiments, W² is C and W³ is N. In embodiments,W⁴ is N. In embodiments, W⁴ is CR¹². In embodiments, Y is O. Inembodiments, Y is NR¹³. In embodiments, W¹ is CH. In embodiments, W⁴ isCH. In embodiments, Y is NH.

In embodiments, the compound has the formula:

wherein W¹ is N or CH. In embodiments, W¹ is N. In embodiments, W¹ isCH.

In embodiments, the compound has the formula:

In embodiments, R³ is independently substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. Inembodiments, R³ is independently substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. Inembodiments, R³ is independently substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. In embodiments, R³ isindependently substituted or unsubstituted fused ring aryl, orsubstituted or unsubstituted fused ring heteroaryl. In embodiments, R³is independently substituted or unsubstituted fused ring heteroaryl. Inembodiments, R³ is independently substituted fused ring heteroaryl.

In embodiments, R³ is

R²⁰ is as described herein. Ring A is an aryl (e.g., phenyl, diphenyl,or fused ring aryl) or a heteroaryl (e.g., monocyclic heteroaryl orfused ring heteroaryl). Ring A may be any of the aryl or heteroarylrings in the embodiments of R³ described herein (e.g., benzoxazolyl,indolyl, phenyl, or naphthyl). The symbol z3 is an integer from 0 to 7.In embodiments, z3 is 0. In embodiments, z3 is 1. In embodiments, z3 is2. In embodiments, z3 is 3. In embodiments, z3 is 4. In embodiments, z3is 5. In embodiments, z3 is 6. In embodiments, z3 is 7.

In embodiments, R³ is independently substituted benzoxazolyl,substituted pyrimidinyl, substituted thiophenyl, substituted furanyl,substituted indolyl, substituted benzoxadiazolyl, substitutedbenzodioxolyl, substituted benzodioxanyl, substituted thianaphthanyl,substituted pyrrolopyridinyl, substituted indazolyl, substitutedquinolinyl, substituted quinoxalinyl, substituted pyridopyrazinyl,substituted quinazolinonyl, substituted benzoisoxazolyl, substitutedimidazopyridinyl, substituted benzofuranyl, substituted benzothiophenyl,substituted phenyl, substituted naphthyl, substituted biphenyl,substituted pyrrolyl, substituted pyrazolyl, substituted imidazolyl,substituted pyrazinyl, substituted oxazolyl, substituted isoxazolyl,substituted thiazolyl, substituted furylthienyl, substituted pyridyl,substituted pyrimidyl, substituted benzothiazolyl, substituted purinyl,substituted benzimidazolyl, substituted isoquinolyl, substitutedthiadiazolyl, substituted oxadiazolyl, substituted pyrrolyl, substituteddiazolyl, substituted triazolyl, substituted tetrazolyl, substitutedbenzothiadiazolyl, substituted isothiazolyl, substitutedpyrazolopyrimidinyl, substituted pyrrolopyrimidinyl, substitutedbenzotriazolyl, or substituted quinolyl. In embodiments, R³ isindependently substituted benzoxazolyl.

In embodiments, R³ is independently substituted benzoxazolyl. Inembodiments, R³ is substituted pyrimidinyl. In embodiments, R³ issubstituted thiophenyl. In embodiments, R³ is substituted furanyl. Inembodiments, R³ is substituted indolyl. In embodiments, R³ issubstituted benzoxadiazolyl. In embodiments, R³ is substitutedbenzodioxolyl. In embodiments, R³ is substituted benzodioxanyl. Inembodiments, R³ is substituted thianaphthanyl. In embodiments, R³ issubstituted pyrrolopyridinyl. In embodiments, R³ is substitutedindazolyl. In embodiments, R³ is substituted quinolinyl. In embodiments,R³ is substituted quinoxalinyl. In embodiments, R³ is substitutedpyridopyrazinyl. In embodiments, R³ is substituted quinazolinonyl. Inembodiments, R³ is substituted benzoisoxazolyl. In embodiments, R³ issubstituted imidazopyridinyl. In embodiments, R³ is substitutedbenzofuranyl. In embodiments, R³ is substituted benzothiophenyl. Inembodiments, R³ is substituted phenyl. In embodiments, R³ is substitutednaphthyl. In embodiments, R³ is substituted biphenyl. In embodiments, R³is substituted pyrrolyl. In embodiments, R³ is substituted pyrazolyl. Inembodiments, R³ is substituted imidazolyl. In embodiments, R³ issubstituted pyrazinyl. In embodiments, R³ is substituted oxazolyl. Inembodiments, R³ is substituted isoxazolyl. In embodiments, R³ issubstituted thiazolyl. In embodiments, R³ is substituted furylthienyl.In embodiments, R³ is substituted pyridyl. In embodiments, R³ issubstituted pyrimidyl. In embodiments, R³ is substituted benzothiazolyl.In embodiments, R³ is substituted purinyl. In embodiments, R³ issubstituted benzimidazolyl. In embodiments, R³ is substitutedisoquinolyl. In embodiments, R³ is substituted thiadiazolyl. Inembodiments, R³ is substituted oxadiazolyl. In embodiments, R³ issubstituted pyrrolyl. In embodiments, R³ is substituted diazolyl. Inembodiments, R³ is substituted triazolyl. In embodiments, R³ issubstituted tetrazolyl. In embodiments, R³ is substitutedbenzothiadiazolyl. In embodiments, R³ is substituted isothiazolyl. Inembodiments, R³ is substituted pyrazolopyrimidinyl. In embodiments, R³is substituted pyrrolopyrimidinyl. In embodiments, R³ is substitutedbenzotriazolyl. In embodiments, R³ is substituted quinolyl. Inembodiments, R³ is independently substituted benzoxazolyl.

In embodiments, R³ is independently unsubstituted benzoxazolyl. Inembodiments, R³ is unsubstituted pyrimidinyl. In embodiments, R³ isunsubstituted thiophenyl. In embodiments, R³ is unsubstituted furanyl.In embodiments, R³ is unsubstituted indolyl. In embodiments, R³ isunsubstituted benzoxadiazolyl. In embodiments, R³ is unsubstitutedbenzodioxolyl. In embodiments, R³ is unsubstituted benzodioxanyl. Inembodiments, R³ is unsubstituted thianaphthanyl. In embodiments, R³ isunsubstituted pyrrolopyridinyl. In embodiments, R³ is unsubstitutedindazolyl. In embodiments, R³ is unsubstituted quinolinyl. Inembodiments, R³ is unsubstituted quinoxalinyl. In embodiments, R³ isunsubstituted pyridopyrazinyl. In embodiments, R³ is unsubstitutedquinazolinonyl. In embodiments, R³ is unsubstituted benzoisoxazolyl. Inembodiments, R³ is unsubstituted imidazopyridinyl. In embodiments, R³ isunsubstituted benzofuranyl. In embodiments, R³ is unsubstitutedbenzothiophenyl. In embodiments, R³ is unsubstituted phenyl. Inembodiments, R³ is unsubstituted naphthyl. In embodiments, R³ isunsubstituted biphenyl. In embodiments, R³ is unsubstituted pyrrolyl. Inembodiments, R³ is unsubstituted pyrazolyl. In embodiments, R³ isunsubstituted imidazolyl. In embodiments, R³ is unsubstituted pyrazinyl.In embodiments, R³ is unsubstituted oxazolyl. In embodiments, R³ isunsubstituted isoxazolyl. In embodiments, R³ is unsubstituted thiazolyl.In embodiments, R³ is unsubstituted furylthienyl. In embodiments, R³ isunsubstituted pyridyl. In embodiments, R³ is unsubstituted pyrimidyl. Inembodiments, R³ is unsubstituted benzothiazolyl. In embodiments, R³ isunsubstituted purinyl. In embodiments, R³ is unsubstitutedbenzimidazolyl. In embodiments, R³ is unsubstituted isoquinolyl. Inembodiments, R³ is unsubstituted thiadiazolyl. In embodiments, R³ isunsubstituted oxadiazolyl. In embodiments, R³ is unsubstituted pyrrolyl.In embodiments, R³ is unsubstituted diazolyl. In embodiments, R³ isunsubstituted triazolyl. In embodiments, R³ is unsubstituted tetrazolyl.In embodiments, R³ is unsubstituted benzothiadiazolyl. In embodiments,R³ is unsubstituted isothiazolyl. In embodiments, R³ is unsubstitutedpyrazolopyrimidinyl. In embodiments, R³ is unsubstitutedpyrrolopyrimidinyl. In embodiments, R³ is unsubstituted benzotriazolyl.In embodiments, R³ is unsubstituted quinolyl. In embodiments, R³ isindependently unsubstituted benzoxazolyl.

In some embodiments of the compounds provided herein, R³ isindependently hydrogen, oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R²⁰-substituted or unsubstituted alkyl, R²⁰-substituted or unsubstitutedheteroalkyl, R²⁰-substituted or unsubstituted cycloalkyl,R²⁰-substituted or unsubstituted heterocycloalkyl, R²⁰-substituted orunsubstituted aryl, or R²⁰-substituted or unsubstituted heteroaryl.

In some embodiments, R³ is substituted with one or more substituentsindependently selected from halogen, —CF₃, —OH, and —NH₂. In someembodiments, R³ is substituted heteroaryl, such as benzoxazolyl orbenzothiazolyl. In some embodiments, R³ is heteroaryl, such asbenzoxazolyl or benzothiazolyl, substituted with one or moresubstituents independently selected from halogen, —CF₃, —OH, and —NH₂.

In embodiments, R³ is independently R²⁰-substituted benzoxazolyl,R²⁰-substituted pyrimidinyl, R²⁰-substituted thiophenyl, R²⁰-substitutedfuranyl, R²⁰-substituted indolyl, R²⁰-substituted benzoxadiazolyl,R²⁰-substituted benzodioxolyl, R²⁰-substituted benzodioxanyl,R²⁰-substituted thianaphthanyl, R²⁰-substituted pyrrolopyridinyl,R²⁰-substituted indazolyl, R²⁰-substituted quinolinyl, R²⁰-substitutedquinoxalinyl, R²⁰-substituted pyridopyrazinyl, R²⁰-substitutedquinazolinonyl, R²⁰-substituted benzoisoxazolyl, R²⁰-substitutedimidazopyridinyl, R²⁰-substituted benzofuranyl, R²⁰-substitutedbenzothiophenyl, R²⁰-substituted phenyl, R²⁰-substituted naphthyl,R²⁰-substituted biphenyl, R²⁰-substituted pyrrolyl, R²⁰-substitutedpyrazolyl, R²⁰-substituted imidazolyl, R²⁰-substituted pyrazinyl,R²⁰-substituted oxazolyl, R²⁰-substituted isoxazolyl, R²⁰-substitutedthiazolyl, R²⁰-substituted furylthienyl, R²⁰-substituted pyridyl,R²⁰-substituted pyrimidyl, R²⁰-substituted benzothiazolyl,R²⁰-substituted purinyl, R²⁰-substituted benzimidazolyl, R²⁰-substitutedisoquinolyl, R²⁰-substituted thiadiazolyl, R²⁰-substituted oxadiazolyl,R²⁰-substituted pyrrolyl, R²⁰-substituted diazolyl, R²⁰-substitutedtriazolyl, R²⁰-substituted tetrazolyl, R²⁰-substitutedbenzothiadiazolyl, R²⁰-substituted isothiazolyl, R²⁰-substitutedpyrazolopyrimidinyl, R²⁰-substituted pyrrolopyrimidinyl, R²⁰-substitutedbenzotriazolyl, or R²⁰-substituted quinolyl. In embodiments, R³ isindependently R²⁰-substituted benzoxazolyl.

In embodiments, R³ is independently R²⁰-substituted benzoxazolyl. Inembodiments, R³ is R²⁰-substituted pyrimidinyl. In embodiments, R³ isR²⁰-substituted thiophenyl. In embodiments, R³ is R²⁰-substitutedfuranyl. In embodiments, R³ is R²⁰-substituted indolyl. In embodiments,R³ is R²⁰-substituted benzoxadiazolyl. In embodiments, R³ isR²⁰-substituted benzodioxolyl. In embodiments, R³ is R²⁰-substitutedbenzodioxanyl. In embodiments, R³ is R²⁰-substituted thianaphthanyl. Inembodiments, R³ is R²⁰-substituted pyrrolopyridinyl. In embodiments, R³is R²⁰-substituted indazolyl. In embodiments, R³ is R²⁰-substitutedquinolinyl. In embodiments, R³ is R²⁰-substituted quinoxalinyl. Inembodiments, R³ is R²⁰-substituted pyridopyrazinyl. In embodiments, R³is R²⁰-substituted quinazolinonyl. In embodiments, R³ is R²⁰-substitutedbenzoisoxazolyl. In embodiments, R³ is R²⁰-substituted imidazopyridinyl.In embodiments, R³ is R²⁰-substituted benzofuranyl. In embodiments, R³is R²⁰-substituted benzothiophenyl. In embodiments, R³ isR²⁰-substituted phenyl. In embodiments, R³ is R²⁰-substituted naphthyl.In embodiments, R³ is R²⁰-substituted biphenyl. In embodiments, R³ isR²⁰-substituted pyrrolyl. In embodiments, R³ is R²⁰-substitutedpyrazolyl. In embodiments, R³ is R²⁰-substituted imidazolyl. Inembodiments, R³ is R²⁰-substituted pyrazinyl. In embodiments, R³ isR²⁰-substituted oxazolyl. In embodiments, R³ is R²⁰-substitutedisoxazolyl. In embodiments, R³ is R²⁰-substituted thiazolyl. Inembodiments, R³ is R²⁰-substituted furylthienyl. In embodiments, R³ isR²⁰-substituted pyridyl. In embodiments, R³ is R²⁰-substitutedpyrimidyl. In embodiments, R³ is R²⁰-substituted benzothiazolyl. Inembodiments, R³ is R²⁰-substituted purinyl. In embodiments, R³ isR²⁰-substituted benzimidazolyl. In embodiments, R³ is R²⁰-substitutedisoquinolyl. In embodiments, R³ is R²⁰-substituted thiadiazolyl. Inembodiments, R³ is R²⁰-substituted oxadiazolyl. In embodiments, R³ isR²⁰-substituted pyrrolyl. In embodiments, R³ is R²⁰-substituteddiazolyl. In embodiments, R³ is R²⁰-substituted triazolyl. Inembodiments, R³ is R²⁰-substituted tetrazolyl. In embodiments, R³ isR²⁰-substituted benzothiadiazolyl. In embodiments, R³ is R²⁰-substitutedisothiazolyl. In embodiments, R³ is R²⁰-substituted pyrazolopyrimidinyl.In embodiments, R³ is R²⁰-substituted pyrrolopyrimidinyl. Inembodiments, R³ is R²⁰-substituted benzotriazolyl. In embodiments, R³ isR²⁰-substituted quinolyl. In embodiments, R³ is independentlyR²⁰-substituted benzoxazolyl.

R²⁰ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R²¹-substituted or unsubstituted alkyl, R²¹-substituted or unsubstitutedheteroalkyl, R²¹-substituted or unsubstituted cycloalkyl,R²¹-substituted or unsubstituted heterocycloalkyl, R²¹-substituted orunsubstituted aryl, or R²¹-substituted or unsubstituted heteroaryl.

In embodiments, R²⁰ is independently —NH₂. In embodiments, R²⁰ isindependently —OH. In embodiments, R²⁰ is independently halogen. Inembodiments, R²⁰ is independently —CN. In embodiments, R²⁰ isindependently oxo. In embodiments, R²⁰ is independently —CF₃. Inembodiments, R²⁰ is independently —COOH. In embodiments, R²⁰ isindependently —CONH₂. In embodiments, R²⁰ is independently —NO₂. Inembodiments, R²⁰ is independently —SH. In embodiments, R²⁰ isindependently —SO₃H. In embodiments, R²⁰ is independently —SO₄H. Inembodiments, R²⁰ is independently —SO₂NH₂. In embodiments, R²⁰ isindependently —NHNH₂. In embodiments, R²⁰ is independently —ONH₂. Inembodiments, R²⁰ is independently —NHC═(O)NHNH₂. In embodiments, R²⁰ isindependently —NHC═(O)NH₂. In embodiments, R²⁰ is independently —NHSO₂H.In embodiments, R²⁰ is independently —NHC═(O)H. In embodiments, R²⁰ isindependently —NHC(O)OH. In embodiments, R²⁰ is independently —NHOH. Inembodiments, R²⁰ is independently —OCF₃. In embodiments, R²⁰ isindependently —OCHF₂. In embodiments, R²⁰ is independently a halogen,—CF₃, —CHF₂, —CH₂F, —CN, —NHNH₂, —NO₂, —NH₂, —C(O)H, —C(O)OH, —C(O)NH₂,—OH, —NHC(O)OH, —OCF₃, —OCHF₂, R²¹-substituted or unsubstituted C₁-C₈alkyl, R²¹-substituted or unsubstituted 2 to 8 membered heteroalkyl,R²¹-substituted or unsubstituted C₃-C₈ cycloalkyl, R²¹-substituted orunsubstituted 3 to 8 membered heterocycloalkyl, R²¹-substituted orunsubstituted C₆-C₁₀ aryl, or R²¹-substituted or unsubstituted 5 to 10membered heteroaryl. In embodiments, R²⁰ is independently a halogen,—CF₃, —CN, —NH₂, —OH, R²¹-substituted or unsubstituted C₁-C₄ alkyl,R²¹-substituted or unsubstituted 2 to 4 membered heteroalkyl,R²¹-substituted or unsubstituted C₃-C₆ cycloalkyl, R²¹-substituted orunsubstituted 3 to 6 membered heterocycloalkyl, R²¹-substituted orunsubstituted phenyl, or R²¹-substituted or unsubstituted 5 to 6membered heteroaryl. In embodiments, R²⁰ is independently a halogen,—CF₃, —CN, —NH₂, —OH, unsubstituted C₁-C₄ alkyl, or unsubstituted 2 to 4membered heteroalkyl. In embodiments, R²⁰ is independently a halogen,—CF₃, unsubstituted methyl, unsubstituted ethyl, unsubstitutedisopropyl, unsubstituted methoxy, or unsubstituted ethoxy. Inembodiments, R²⁰ is independently unsubstituted methyl. In embodiments,R²⁰ is independently unsubstituted ethyl. In embodiments, R²⁰ isindependently unsubstituted methoxy. In embodiments, R²⁰ isindependently unsubstituted ethoxy. In embodiments, R²⁰ is independently—CCl₃. In embodiments, R²⁰ is independently —CBr₃. In embodiments, R²⁰is independently —Cl₃. In embodiments, R²⁰ is independently —F. Inembodiments, R²⁰ is independently —Cl. In embodiments, R²⁰ isindependently —Br. In embodiments, R²⁰ is independently —I.

R²¹ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R²²-substituted or unsubstituted alkyl, R²²-substituted or unsubstitutedheteroalkyl, R²²-substituted or unsubstituted cycloalkyl,R²²-substituted or unsubstituted heterocycloalkyl, R²²-substituted orunsubstituted aryl, or R²²-substituted or unsubstituted heteroaryl.

In embodiments, R²¹ is independently —NH₂. In embodiments, R²¹ isindependently —OH. In embodiments, R²¹ is independently halogen. Inembodiments, R²¹ is independently —CN. In embodiments, R²¹ isindependently oxo. In embodiments, R²¹ is independently —CF₃. Inembodiments, R²¹ is independently —COOH. In embodiments, R²¹ isindependently —CONH₂. In embodiments, R²¹ is independently —NO₂. Inembodiments, R²¹ is independently —SH. In embodiments, R²¹ isindependently —SO₃H. In embodiments, R²¹ is independently —SO₄H. Inembodiments, R²¹ is independently —SO₂NH₂. In embodiments, R²¹ isindependently —NHNH₂. In embodiments, R²¹ is independently —ONH₂. Inembodiments, R²¹ is independently —NHC═(O)NHNH₂. In embodiments, R²¹ isindependently —NHC═(O)NH₂. In embodiments, R²¹ is independently —NHSO₂H.In embodiments, R²¹ is independently —NHC═(O)H. In embodiments, R²¹ isindependently —NHC(O)OH. In embodiments, R²¹ is independently —NHOH. Inembodiments, R²¹ is independently —OCF₃. In embodiments, R²¹ isindependently —OCHF₂. In embodiments, R²¹ is independently a halogen,—CF₃, —CHF₂, —CH₂F, —CN, —NHNH₂, —NO₂, —NH₂, —C(O)H, —C(O)OH, —C(O)NH₂,—OH, —NHC(O)OH, —OCF₃, —OCHF₂, R²²-substituted or unsubstituted C₁-C₈alkyl, R²²-substituted or unsubstituted 2 to 8 membered heteroalkyl,R²²-substituted or unsubstituted C₃-C₈ cycloalkyl, R²²-substituted orunsubstituted 3 to 8 membered heterocycloalkyl, R²²-substituted orunsubstituted C₆-C₁₀ aryl, or R²²-substituted or unsubstituted 5 to 10membered heteroaryl. In embodiments, R²¹ is independently a halogen,—CF₃, —CN, —NH₂, —OH, R²²-substituted or unsubstituted C₁-C₄ alkyl,R²²-substituted or unsubstituted 2 to 4 membered heteroalkyl,R²²-substituted or unsubstituted C₃-C₆ cycloalkyl, R²²-substituted orunsubstituted 3 to 6 membered heterocycloalkyl, R²²-substituted orunsubstituted phenyl, or R²²-substituted or unsubstituted 5 to 6membered heteroaryl. In embodiments, R²¹ is independently a halogen,—CF₃, —CN, —NH₂, —OH, unsubstituted C₁-C₄ alkyl, or unsubstituted 2 to 4membered heteroalkyl. In embodiments, R²¹ is independently a halogen,—CF₃, unsubstituted methyl, unsubstituted ethyl, unsubstitutedisopropyl, unsubstituted methoxy, or unsubstituted ethoxy. Inembodiments, R²¹ is independently unsubstituted methyl. In embodiments,R²¹ is independently unsubstituted ethyl. In embodiments, R²¹ isindependently unsubstituted methoxy. In embodiments, R²¹ isindependently unsubstituted ethoxy. In embodiments, R²¹ is independently—CCl₃. In embodiments, R²¹ is independently —CBr₃. In embodiments, R²¹is independently —Cl₃. In embodiments, R²¹ is independently —F. Inembodiments, R²¹ is independently —Cl. In embodiments, R²¹ isindependently —Br. In embodiments, R²¹ is independently —I.

In embodiments, R⁷ is independently hydrogen, halogen, —CF₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCF₃, —OCHF₂, R³⁸-substituted or unsubstituted alkyl, R³⁸-substitutedor unsubstituted heteroalkyl, R³⁸-substituted or unsubstitutedcycloalkyl, R³⁸-substituted or unsubstituted heterocycloalkyl,R³⁸-substituted or unsubstituted aryl, or R³⁸-substituted orunsubstituted heteroaryl.

In embodiments, R⁷ is independently hydrogen, —CF₃, —CN, —COOH, —CONH₂,R³⁸-substituted or unsubstituted alkyl, R³⁸-substituted or unsubstitutedheteroalkyl, R³⁸-substituted or unsubstituted cycloalkyl,R³⁸-substituted or unsubstituted heterocycloalkyl, R³⁸-substituted orunsubstituted aryl, or R³⁸-substituted or unsubstituted heteroaryl. Inembodiments, R⁷ is independently an R³⁸-substituted or unsubstitutedC₁-C₄ alkyl, R³⁸-substituted or unsubstituted 2 to 4 memberedheteroalkyl, R³⁸-substituted or unsubstituted C₃-C₆ cycloalkyl,R³⁸-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R³⁸-substituted or unsubstituted phenyl, or R³⁸-substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R⁷ isindependently an unsubstituted C₁-C₄ alkyl, unsubstituted 2 to 4membered heteroalkyl, unsubstituted C₃-C₆ cycloalkyl, unsubstituted 3 to6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to6 membered heteroaryl. In embodiments, R⁷ is independently anunsubstituted C₁-C₄ alkyl. In embodiments, R⁷ is independently anunsubstituted methyl. In embodiments, R⁷ is independently anunsubstituted ethyl. In embodiments, R⁷ is independently anunsubstituted isopropyl. In embodiments, R⁷ is independently anunsubstituted tert-butyl. In embodiments, R⁷ is independently hydrogen.

R³⁸ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, —S(O)₂CHCH₂,—NHS(O)₂CHCH₂, R³⁹-substituted or unsubstituted alkyl, R³⁹-substitutedor unsubstituted heteroalkyl, R³⁹-substituted or unsubstitutedcycloalkyl, R³⁹ substituted or unsubstituted heterocycloalkyl,R³⁹-substituted or unsubstituted aryl, or R³⁹-substituted orunsubstituted heteroaryl.

In embodiments, R³⁸ is independently —NH₂. In embodiments, R³⁸ isindependently —OH. In embodiments, R³⁸ is independently halogen. Inembodiments, R³⁸ is independently —CN. In embodiments, R³⁸ isindependently oxo. In embodiments, R³⁸ is independently —CF₃. Inembodiments, R³⁸ is independently —COOH. In embodiments, R³⁸ isindependently —CONH₂. In embodiments, R³⁸ is independently —NO₂. Inembodiments, R³⁸ is independently —SH. In embodiments, R³⁸ isindependently —SO₃H. In embodiments, R³⁸ is independently —SO₄H. Inembodiments, R³⁸ is independently —SO₂NH₂. In embodiments, R³⁸ isindependently —NHNH₂. In embodiments, R³⁸ is independently —ONH₂. Inembodiments, R³⁸ is independently —NHC═(O)NHNH₂. In embodiments, R³⁸ isindependently —NHC═(O) NH₂. In embodiments, R³⁸ is independently—NHSO₂H. In embodiments, R³⁸ is independently —NHC═(O)H. In embodiments,R³⁸ is independently —NHC(O)—OH. In embodiments, R³⁸ is independently—NHOH. In embodiments, R³⁸ is independently —OCF₃. In embodiments, R³⁸is independently —OCHF₂. In embodiments, R³⁸ is independently —CCl₃. Inembodiments, R³⁸ is independently —CBr₃. In embodiments, R³⁸ isindependently —Cl₃. In embodiments, R³⁸ is independently —F. Inembodiments, R³⁸ is independently —Cl. In embodiments, R³⁸ isindependently —Br. In embodiments, R³⁸ is independently —I. Inembodiments, R³⁸ is independently R³⁹-substituted C₁-C₄ alkyl. Inembodiments, R³⁸ is independently R³⁹-substituted 2 to 4 memberedheteroalkyl. In embodiments, R³⁸ is independently R³⁹-substituted C₃-C₆cycloalkyl. In embodiments, R³⁸ is independently R³⁹-substituted 3 to 6membered heterocycloalkyl. In embodiments, R³⁸ is independentlyR³⁹-substituted phenyl. In embodiments, R³⁸ is independentlyR³⁹-substituted 5 to 6 membered heteroaryl. In embodiments, R³⁸ isindependently unsubstituted C₁-C₄ alkyl. In embodiments, R³⁸ isindependently unsubstituted 2 to 4 membered heteroalkyl. In embodiments,R³⁸ is independently unsubstituted C₃-C₆ cycloalkyl. In embodiments, R³⁸is independently unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R³⁸ is independently unsubstituted phenyl. In embodiments,R³⁸ is independently unsubstituted 5 to 6 membered heteroaryl.

R³⁹ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, —S(O)₂CHCH₂,—NHS(O)₂CHCH₂, R⁴⁰-substituted or unsubstituted alkyl, R⁴⁰-substitutedor unsubstituted heteroalkyl, R⁴⁰-substituted or unsubstitutedcycloalkyl, R⁴⁰-substituted or unsubstituted heterocycloalkyl,R⁴⁰-substituted or unsubstituted aryl, or R⁴⁰-substituted orunsubstituted heteroaryl.

In embodiments, R³⁹ is independently —NH₂. In embodiments, R³⁹ isindependently —OH. In embodiments, R³⁹ is independently halogen. Inembodiments, R³⁹ is independently —CN. In embodiments, R³⁹ isindependently oxo. In embodiments, R³⁹ is independently —CF₃. Inembodiments, R³⁹ is independently —COOH. In embodiments, R³⁹ isindependently —CONH₂. In embodiments, R³⁹ is independently —NO₂. Inembodiments, R³⁹ is independently —SH. In embodiments, R³⁹ isindependently —SO₃H. In embodiments, R³⁹ is independently —SO₄H. Inembodiments, R³⁹ is independently —SO₂NH₂. In embodiments, R³⁹ isindependently —NHNH₂. In embodiments, R³⁹ is independently —ONH₂. Inembodiments, R³⁹ is independently —NHC═(O)NHNH₂. In embodiments, R³⁹ isindependently —NHC═(O) NH₂. In embodiments, R³⁹ is independently—NHSO₂H. In embodiments, R³⁹ is independently —NHC═(O)H. In embodiments,R³⁹ is independently —NHC(O)—OH. In embodiments, R³⁹ is independently—NHOH. In embodiments, R³⁹ is independently —OCF₃. In embodiments, R³⁹is independently —OCHF₂. In embodiments, R³⁹ is independently —CCl₃. Inembodiments, R³⁹ is independently —CBr₃. In embodiments, R³⁹ isindependently —Cl₃. In embodiments, R³⁹ is independently —F. Inembodiments, R³⁹ is independently —Cl. In embodiments, R³⁹ isindependently —Br. In embodiments, R³⁹ is independently —I. Inembodiments, R³⁹ is independently R⁴⁰-substituted C₁-C₄ alkyl. Inembodiments, R³⁹ is independently R⁴⁰-substituted 2 to 4 memberedheteroalkyl. In embodiments, R³⁹ is independently R⁴⁰-substituted C₃-C₆cycloalkyl. In embodiments, R³⁹ is independently R⁴⁰-substituted 3 to 6membered heterocycloalkyl. In embodiments, R³⁹ is independentlyR⁴⁰-substituted phenyl. In embodiments, R³⁹ is independentlyR⁴⁰-substituted 5 to 6 membered heteroaryl. In embodiments, R³⁹ isindependently unsubstituted C₁-C₄ alkyl. In embodiments, R³⁹ isindependently unsubstituted 2 to 4 membered heteroalkyl. In embodiments,R³⁹ is independently unsubstituted C₃-C₆ cycloalkyl. In embodiments, R³⁹is independently unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R³⁹ is independently unsubstituted phenyl. In embodiments,R³⁹ is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, R⁸ is independently hydrogen, halogen, —CF₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCF₃, —OCHF₂, R⁴¹-substituted or unsubstituted alkyl, R⁴¹-substitutedor unsubstituted heteroalkyl, R⁴¹-substituted or unsubstitutedcycloalkyl, R⁴¹-substituted or unsubstituted heterocycloalkyl,R⁴¹-substituted or unsubstituted aryl, or R⁴¹-substituted orunsubstituted heteroaryl.

In embodiments, R⁸ is independently hydrogen, —CF₃, —CN, —COOH, —CONH₂,R⁴¹-substituted or unsubstituted alkyl, R⁴¹-substituted or unsubstitutedheteroalkyl, R⁴¹-substituted or unsubstituted cycloalkyl,R⁴¹-substituted or unsubstituted heterocycloalkyl, R⁴¹-substituted orunsubstituted aryl, or R⁴¹-substituted or unsubstituted heteroaryl. Inembodiments, R⁸ is independently an R⁴¹-substituted or unsubstitutedC₁-C₄ alkyl, R⁴¹-substituted or unsubstituted 2 to 4 memberedheteroalkyl, R⁴¹-substituted or unsubstituted C₃-C₆ cycloalkyl,R⁴¹-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R⁴¹-substituted or unsubstituted phenyl, or R⁴¹-substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R⁴¹ isindependently an unsubstituted C₁-C₄ alkyl, unsubstituted 2 to 4membered heteroalkyl, unsubstituted C₃-C₆ cycloalkyl, unsubstituted 3 to6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to6 membered heteroaryl. In embodiments, R⁸ is independently anunsubstituted C₁-C₄ alkyl. In embodiments, R⁴¹ is independently anunsubstituted methyl. In embodiments, R⁸ is independently anunsubstituted ethyl. In embodiments, R⁸ is independently anunsubstituted isopropyl. In embodiments, R⁸ is independently anunsubstituted tert-butyl. In embodiments, R⁸ is independently hydrogen.

R⁴¹ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, —S(O)₂CHCH₂,—NHS(O)₂CHCH₂, R⁴²-substituted or unsubstituted alkyl, R⁴²-substitutedor unsubstituted heteroalkyl, R⁴²-substituted or unsubstitutedcycloalkyl, R⁴² substituted or unsubstituted heterocycloalkyl,R⁴²-substituted or unsubstituted aryl, or R⁴²-substituted orunsubstituted heteroaryl.

In embodiments, R⁴¹ is independently —NH₂. In embodiments, R⁴¹ isindependently —OH. In embodiments, R⁴¹ is independently halogen. Inembodiments, R⁴¹ is independently —CN. In embodiments, R⁴¹ isindependently oxo. In embodiments, R⁴¹ is independently —CF₃. Inembodiments, R⁴¹ is independently —COOH. In embodiments, R⁴¹ isindependently —CONH₂. In embodiments, R⁴¹ is independently —NO₂. Inembodiments, R⁴¹ is independently —SH. In embodiments, R⁴¹ isindependently —SO₃H. In embodiments, R⁴¹ is independently —SO₄H. Inembodiments, R⁴¹ is independently —SO₂NH₂. In embodiments, R⁴¹ isindependently —NHNH₂. In embodiments, R⁴¹ is independently —ONH₂. Inembodiments, R⁴¹ is independently —NHC═(O)NHNH₂. In embodiments, R⁴¹ isindependently —NHC═(O) NH₂. In embodiments, R⁴¹ is independently—NHSO₂H. In embodiments, R⁴¹ is independently —NHC═(O)H. In embodiments,R⁴¹ is independently —NHC(O)—OH. In embodiments, R⁴¹ is independently—NHOH. In embodiments, R⁴¹ is independently —OCF₃. In embodiments, R⁴¹is independently —OCHF₂. In embodiments, R⁴¹ is independently —CCl₃. Inembodiments, R⁴¹ is independently —CBr₃. In embodiments, R⁴¹ isindependently —Cl₃. In embodiments, R⁴¹ is independently —F. Inembodiments, R⁴¹ is independently —Cl. In embodiments, R⁴¹ isindependently —Br. In embodiments, R⁴¹ is independently —I. Inembodiments, R⁴¹ is independently R⁴²-substituted C₁-C₄ alkyl. Inembodiments, R⁴¹ is independently R⁴²-substituted 2 to 4 memberedheteroalkyl. In embodiments, R⁴¹ is independently R⁴²-substituted C₃-C₆cycloalkyl. In embodiments, R⁴¹ is independently R⁴²-substituted 3 to 6membered heterocycloalkyl. In embodiments, R⁴¹ is independentlyR⁴²-substituted phenyl. In embodiments, R⁴¹ is independentlyR⁴²-substituted 5 to 6 membered heteroaryl. In embodiments, R⁴¹ isindependently unsubstituted C₁-C₄ alkyl. In embodiments, R⁴¹ isindependently unsubstituted 2 to 4 membered heteroalkyl. In embodiments,R⁴¹ is independently unsubstituted C₃-C₆ cycloalkyl. In embodiments, R⁴¹is independently unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R⁴¹ is independently unsubstituted phenyl. In embodiments,R⁴¹ is independently unsubstituted 5 to 6 membered heteroaryl.

R⁴² is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, —S(O)₂CHCH₂,—NHS(O)₂CHCH₂, R⁴³-substituted or unsubstituted alkyl, R⁴³-substitutedor unsubstituted heteroalkyl, R⁴³-substituted or unsubstitutedcycloalkyl, R⁴³-substituted or unsubstituted heterocycloalkyl,R⁴³-substituted or unsubstituted aryl, or R⁴³-substituted orunsubstituted heteroaryl.

In embodiments, R⁴² is independently —NH₂. In embodiments, R⁴² isindependently —OH. In embodiments, R⁴² is independently halogen. Inembodiments, R⁴² is independently —CN. In embodiments, R⁴² isindependently oxo. In embodiments, R⁴² is independently —CF₃. Inembodiments, R⁴² is independently —COOH. In embodiments, R⁴² isindependently —CONH₂. In embodiments, R⁴² is independently —NO₂. Inembodiments, R⁴² is independently —SH. In embodiments, R⁴² isindependently —SO₃H. In embodiments, R⁴² is independently —SO₄H. Inembodiments, R⁴² is independently —SO₂NH₂. In embodiments, R⁴² isindependently —NHNH₂. In embodiments, R⁴² is independently —ONH₂. Inembodiments, R⁴² is independently —NHC═(O)NHNH₂. In embodiments, R⁴² isindependently —NHC═(O) NH₂. In embodiments, R⁴² is independently—NHSO₂H. In embodiments, R⁴² is independently —NHC═(O)H. In embodiments,R⁴² is independently —NHC(O)—OH. In embodiments, R⁴² is independently—NHOH. In embodiments, R⁴² is independently —OCF₃. In embodiments, R⁴²is independently —OCHF₂. In embodiments, R⁴² is independently —CCl₃. Inembodiments, R⁴² is independently —CBr₃. In embodiments, R⁴² isindependently —Cl₃. In embodiments, R⁴² is independently —F. Inembodiments, R⁴² is independently —Cl. In embodiments, R⁴² isindependently —Br. In embodiments, R⁴² is independently —I. Inembodiments, R⁴² is independently R⁴³-substituted C₁-C₄ alkyl. Inembodiments, R⁴² is independently R⁴³-substituted 2 to 4 memberedheteroalkyl. In embodiments, R⁴² is independently R⁴³-substituted C₃-C₆cycloalkyl. In embodiments, R⁴² is independently R⁴³-substituted 3 to 6membered heterocycloalkyl. In embodiments, R⁴² is independentlyR⁴³-substituted phenyl. In embodiments, R⁴² is independentlyR⁴³-substituted 5 to 6 membered heteroaryl. In embodiments, R⁴² isindependently unsubstituted C₁-C₄ alkyl. In embodiments, R⁴² isindependently unsubstituted 2 to 4 membered heteroalkyl. In embodiments,R⁴² is independently unsubstituted C₃-C₆ cycloalkyl. In embodiments, R⁴²is independently unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R⁴² is independently unsubstituted phenyl. In embodiments,R⁴² is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, R⁹ is independently hydrogen, halogen, —CF₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCF₃, —OCHF₂, R⁴⁴-substituted or unsubstituted alkyl, R⁴⁴-substitutedor unsubstituted heteroalkyl, R⁴⁴-substituted or unsubstitutedcycloalkyl, R⁴⁴-substituted or unsubstituted heterocycloalkyl,R⁴⁴-substituted or unsubstituted aryl, or R⁴⁴-substituted orunsubstituted heteroaryl.

In embodiments, R⁹ is independently hydrogen, —CF₃, —CN, —COOH, —CONH₂,R⁴⁴-substituted or unsubstituted alkyl, R⁴⁴-substituted or unsubstitutedheteroalkyl, R⁴⁴-substituted or unsubstituted cycloalkyl,R⁴⁴-substituted or unsubstituted heterocycloalkyl, R⁴⁴-substituted orunsubstituted aryl, or R⁴⁴-substituted or unsubstituted heteroaryl. Inembodiments, R⁹ is independently an R⁴⁴-substituted or unsubstitutedC₁-C₄ alkyl, R⁴-substituted or unsubstituted 2 to 4 memberedheteroalkyl, R⁴⁴-substituted or unsubstituted C₃-C₆ cycloalkyl,R⁴⁴-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R⁴-substituted or unsubstituted phenyl, or R⁴-substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R⁹ isindependently an unsubstituted C₁-C₄ alkyl, unsubstituted 2 to 4membered heteroalkyl, unsubstituted C₃-C₆ cycloalkyl, unsubstituted 3 to6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to6 membered heteroaryl. In embodiments, R⁹ is independently anunsubstituted C₁-C₄ alkyl. In embodiments, R⁹ is independently anunsubstituted methyl. In embodiments, R⁹ is independently anunsubstituted ethyl. In embodiments, R⁹ is independently anunsubstituted isopropyl. In embodiments, R⁹ is independently anunsubstituted tert-butyl. In embodiments, R⁹ is independently hydrogen.

R⁴ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁴⁵-substituted or unsubstituted alkyl, R⁴⁵-substituted or unsubstitutedheteroalkyl, R⁴⁵-substituted or unsubstituted cycloalkyl, R⁴⁵substituted or unsubstituted heterocycloalkyl, R⁴⁵-substituted orunsubstituted aryl, or R⁴⁵-substituted or unsubstituted heteroaryl.

In embodiments, R⁴⁴ is independently —NH₂. In embodiments, R⁴⁴ isindependently —OH. In embodiments, R⁴⁴ is independently halogen. Inembodiments, R⁴⁴ is independently —CN. In embodiments, R⁴⁴ isindependently oxo. In embodiments, R⁴ is independently —CF₃. Inembodiments, R⁴⁴ is independently —COOH. In embodiments, R⁴⁴ isindependently —CONH₂. In embodiments, R⁴⁴ is independently —NO₂. Inembodiments, R⁴ is independently —SH. In embodiments, R⁴⁴ isindependently —SO₃H. In embodiments, R⁴⁴ is independently —SO₄H. Inembodiments, R⁴⁴ is independently —SO₂NH₂. In embodiments, R⁴⁴ isindependently —NHNH₂. In embodiments, R⁴⁴ is independently —ONH₂. Inembodiments, R⁴⁴ is independently —NHC═(O)NHNH₂. In embodiments, R⁴ isindependently —NHC═(O) NH₂. In embodiments, R⁴ is independently —NHSO₂H.In embodiments, R⁴⁴ is independently —NHC═(O)H. In embodiments, R⁴⁴ isindependently —NHC(O)—OH. In embodiments, R⁴⁴ is independently —NHOH. Inembodiments, R⁴⁴ is independently —OCF₃. In embodiments, R⁴ isindependently —OCHF₂. In embodiments, R⁴⁴ is independently —CCl₃. Inembodiments, R⁴ is independently —CBr₃. In embodiments, R⁴⁴ isindependently —Cl₃. In embodiments, R⁴⁴ is independently —F. Inembodiments, R⁴⁴ is independently —Cl. In embodiments, R⁴⁴ isindependently —Br. In embodiments, R⁴⁴ is independently —I. Inembodiments, R⁴ is independently R⁴⁵-substituted C₁-C₄ alkyl. Inembodiments, R⁴ is independently R⁴⁵-substituted 2 to 4 memberedheteroalkyl. In embodiments, R⁴⁴ is independently R⁴⁵-substituted C₃-C₆cycloalkyl. In embodiments, R⁴⁴ is independently R⁴⁵-substituted 3 to 6membered heterocycloalkyl. In embodiments, R⁴ is independentlyR⁴⁵-substituted phenyl. In embodiments, R⁴ is independentlyR⁴⁵-substituted 5 to 6 membered heteroaryl. In embodiments, R⁴ isindependently unsubstituted C₁-C₄ alkyl. In embodiments, R⁴⁴ isindependently unsubstituted 2 to 4 membered heteroalkyl. In embodiments,R⁴⁴ is independently unsubstituted C₃-C₆ cycloalkyl. In embodiments, R⁴⁴is independently unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R⁴⁴ is independently unsubstituted phenyl. In embodiments,R⁴⁴ is independently unsubstituted 5 to 6 membered heteroaryl.

R⁴⁵ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁴⁶-substituted or unsubstituted alkyl, R⁴⁶-substituted or unsubstitutedheteroalkyl, R⁴⁶-substituted or unsubstituted cycloalkyl,R⁴⁶-substituted or unsubstituted heterocycloalkyl, R⁴⁶-substituted orunsubstituted aryl, or R⁴⁶-substituted or unsubstituted heteroaryl.

In embodiments, R⁴⁵ is independently —NH₂. In embodiments, R⁴⁵ isindependently —OH. In embodiments, R⁴⁵ is independently halogen. Inembodiments, R⁴⁵ is independently —CN. In embodiments, R⁴⁵ isindependently oxo. In embodiments, R⁴⁵ is independently —CF₃. Inembodiments, R⁴⁵ is independently —COOH. In embodiments, R⁴⁵ isindependently —CONH₂. In embodiments, R⁴⁵ is independently —NO₂. Inembodiments, R⁴⁵ is independently —SH. In embodiments, R⁴⁵ isindependently —SO₃H. In embodiments, R⁴⁵ is independently —SO₄H. Inembodiments, R⁴⁵ is independently —SO₂NH₂. In embodiments, R⁴⁵ isindependently —NHNH₂. In embodiments, R⁴⁵ is independently —ONH₂. Inembodiments, R⁴⁵ is independently —NHC═(O)NHNH₂. In embodiments, R⁴⁵ isindependently —NHC═(O) NH₂. In embodiments, R⁴⁵ is independently—NHSO₂H. In embodiments, R⁴⁵ is independently —NHC═(O)H. In embodiments,R⁴⁵ is independently —NHC(O)—OH. In embodiments, R⁴⁵ is independently—NHOH. In embodiments, R⁴⁵ is independently —OCF₃. In embodiments, R⁴⁵is independently —OCHF₂. In embodiments, R⁴⁵ is independently —CCl₃. Inembodiments, R⁴⁵ is independently —CBr₃. In embodiments, R⁴⁵ isindependently —Cl₃. In embodiments, R⁴⁵ is independently —F. Inembodiments, R⁴⁵ is independently —Cl. In embodiments, R⁴⁵ isindependently —Br. In embodiments, R⁴⁵ is independently —I. Inembodiments, R⁴⁵ is independently R⁴⁶-substituted C₁-C₄ alkyl. Inembodiments, R⁴⁵ is independently R⁴⁶-substituted 2 to 4 memberedheteroalkyl. In embodiments, R⁴⁵ is independently R⁴⁶-substituted C₃-C₆cycloalkyl. In embodiments, R⁴⁵ is independently R⁴⁶-substituted 3 to 6membered heterocycloalkyl. In embodiments, R⁴⁵ is independentlyR⁴⁶-substituted phenyl. In embodiments, R⁴⁵ is independentlyR⁴⁶-substituted 5 to 6 membered heteroaryl. In embodiments, R⁴⁵ isindependently unsubstituted C₁-C₄ alkyl. In embodiments, R⁴⁵ isindependently unsubstituted 2 to 4 membered heteroalkyl. In embodiments,R⁴⁵ is independently unsubstituted C₃-C₆ cycloalkyl. In embodiments, R⁴⁵is independently unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R⁴⁵ is independently unsubstituted phenyl. In embodiments,R⁴⁵ is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, R¹⁰ is independently hydrogen, halogen, —CF₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCF₃, —OCHF₂, R⁴⁷-substituted or unsubstituted alkyl, R⁴⁷-substitutedor unsubstituted heteroalkyl, R⁴⁷-substituted or unsubstitutedcycloalkyl, R⁴⁷-substituted or unsubstituted heterocycloalkyl,R⁴⁷-substituted or unsubstituted aryl, or R⁴⁷-substituted orunsubstituted heteroaryl.

In embodiments, R¹⁰ is independently hydrogen, —CF₃, —CN, —COOH, —CONH₂,R⁴⁷-substituted or unsubstituted alkyl, R⁴⁷-substituted or unsubstitutedheteroalkyl, R⁴⁷-substituted or unsubstituted cycloalkyl,R⁴⁷-substituted or unsubstituted heterocycloalkyl, R⁴⁷-substituted orunsubstituted aryl, or R⁴⁷-substituted or unsubstituted heteroaryl. Inembodiments, R¹⁰ is independently an R⁴⁷-substituted or unsubstitutedC₁-C₄ alkyl, R⁴⁷-substituted or unsubstituted 2 to 4 memberedheteroalkyl, R⁴⁷-substituted or unsubstituted C₃-C₆ cycloalkyl,R⁴⁷-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R⁴⁷-substituted or unsubstituted phenyl, or R⁴⁷-substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R¹⁰ isindependently an unsubstituted C₁-C₄ alkyl, unsubstituted 2 to 4membered heteroalkyl, unsubstituted C₃-C₆ cycloalkyl, unsubstituted 3 to6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to6 membered heteroaryl. In embodiments, R¹⁰ is independently anunsubstituted C₁-C₄ alkyl. In embodiments, R¹⁰ is independently anunsubstituted methyl. In embodiments, R¹⁰ is independently anunsubstituted ethyl. In embodiments, R¹⁰ is independently anunsubstituted isopropyl. In embodiments, R¹⁰ is independently anunsubstituted tert-butyl. In embodiments, R¹⁰ is independently hydrogen.

R⁴⁷ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁴⁸-substituted or unsubstituted alkyl, R⁴⁸-substituted or unsubstitutedheteroalkyl, R⁴⁸-substituted or unsubstituted cycloalkyl, R⁴⁸substituted or unsubstituted heterocycloalkyl, R⁴⁸-substituted orunsubstituted aryl, or R⁴⁸-substituted or unsubstituted heteroaryl.

In embodiments, R⁴⁷ is independently —NH₂. In embodiments, R⁴⁷ isindependently —OH. In embodiments, R⁴⁷ is independently halogen. Inembodiments, R⁴⁷ is independently —CN. In embodiments, R⁴⁷ isindependently oxo. In embodiments, R⁴⁷ is independently —CF₃. Inembodiments, R⁴⁷ is independently —COOH. In embodiments, R⁴⁷ isindependently —CONH₂. In embodiments, R⁴⁷ is independently —NO₂. Inembodiments, R⁴⁷ is independently —SH. In embodiments, R⁴⁷ isindependently —SO₃H. In embodiments, R⁴⁷ is independently —SO₄H. Inembodiments, R⁴⁷ is independently —SO₂NH₂. In embodiments, R⁴⁷ isindependently —NHNH₂. In embodiments, R⁴⁷ is independently —ONH₂. Inembodiments, R⁴⁷ is independently —NHC═(O)NHNH₂. In embodiments, R⁴⁷ isindependently —NHC═(O) NH₂. In embodiments, R⁴⁷ is independently—NHSO₂H. In embodiments, R⁴⁷ is independently —NHC═(O)H. In embodiments,R⁴⁷ is independently —NHC(O)—OH. In embodiments, R⁴⁷ is independently—NHOH. In embodiments, R⁴⁷ is independently —OCF₃. In embodiments, R⁴⁷is independently —OCHF₂. In embodiments, R⁴⁷ is independently —CCl₃. Inembodiments, R⁴⁷ is independently —CBr₃. In embodiments, R⁴⁷ isindependently —Cl₃. In embodiments, R⁴⁷ is independently —F. Inembodiments, R⁴⁷ is independently —Cl. In embodiments, R⁴⁷ isindependently —Br. In embodiments, R⁴⁷ is independently —I. Inembodiments, R⁴⁷ is independently R⁴⁸-substituted C₁-C₄ alkyl. Inembodiments, R⁴⁷ is independently R⁴⁸-substituted 2 to 4 memberedheteroalkyl. In embodiments, R⁴⁷ is independently R⁴⁸-substituted C₃-C₆cycloalkyl. In embodiments, R⁴⁷ is independently R⁴⁸-substituted 3 to 6membered heterocycloalkyl. In embodiments, R⁴⁷ is independentlyR⁴⁸-substituted phenyl. In embodiments, R⁴⁷ is independentlyR⁴⁸-substituted 5 to 6 membered heteroaryl. In embodiments, R⁴⁷ isindependently unsubstituted C₁-C₄ alkyl. In embodiments, R⁴⁷ isindependently unsubstituted 2 to 4 membered heteroalkyl. In embodiments,R⁴⁷ is independently unsubstituted C₃-C₆ cycloalkyl. In embodiments, R⁴⁷is independently unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R⁴⁷ is independently unsubstituted phenyl. In embodiments,R⁴⁷ is independently unsubstituted 5 to 6 membered heteroaryl.

R⁴⁸ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁴⁹-substituted or unsubstituted alkyl, R⁴⁹-substituted or unsubstitutedheteroalkyl, R⁴⁹-substituted or unsubstituted cycloalkyl,R⁴⁹-substituted or unsubstituted heterocycloalkyl, R⁴⁹-substituted orunsubstituted aryl, or R⁴⁹-substituted or unsubstituted heteroaryl.

In embodiments, R⁴⁸ is independently —NH₂. In embodiments, R⁴⁸ isindependently —OH. In embodiments, R⁴⁸ is independently halogen. Inembodiments, R⁴⁸ is independently —CN. In embodiments, R⁴⁸ isindependently oxo. In embodiments, R⁴⁸ is independently —CF₃. Inembodiments, R⁴⁸ is independently —COOH. In embodiments, R⁴⁸ isindependently —CONH₂. In embodiments, R⁴⁸ is independently —NO₂. Inembodiments, R⁴⁸ is independently —SH. In embodiments, R⁴⁸ isindependently —SO₃H. In embodiments, R⁴⁸ is independently —SO₄H. Inembodiments, R⁴⁸ is independently —SO₂NH₂. In embodiments, R⁴⁸ isindependently —NHNH₂. In embodiments, R⁴⁸ is independently —ONH₂. Inembodiments, R⁴⁸ is independently —NHC═(O)NHNH₂. In embodiments, R⁴⁸ isindependently —NHC═(O) NH₂. In embodiments, R⁴⁸ is independently—NHSO₂H. In embodiments, R⁴⁸ is independently —NHC═(O)H. In embodiments,R⁴⁸ is independently —NHC(O)—OH. In embodiments, R⁴⁸ is independently—NHOH. In embodiments, R⁴⁸ is independently —OCF₃. In embodiments, R⁴⁸is independently —OCHF₂. In embodiments, R⁴⁸ is independently —CCl₃. Inembodiments, R⁴⁸ is independently —CBr₃. In embodiments, R⁴⁸ isindependently —Cl₃. In embodiments, R⁴⁸ is independently —F. Inembodiments, R⁴⁸ is independently —Cl. In embodiments, R⁴⁸ isindependently —Br. In embodiments, R⁴⁸ is independently —I. Inembodiments, R⁴⁸ is independently R⁴⁹-substituted C₁-C₄ alkyl. Inembodiments, R⁴⁸ is independently R⁴⁹-substituted 2 to 4 memberedheteroalkyl. In embodiments, R⁴⁸ is independently R⁴⁹-substituted C₃-C₆cycloalkyl. In embodiments, R⁴⁸ is independently R⁴⁹-substituted 3 to 6membered heterocycloalkyl. In embodiments, R⁴⁸ is independentlyR⁴⁹-substituted phenyl. In embodiments, R⁴⁸ is independentlyR⁴⁹-substituted 5 to 6 membered heteroaryl. In embodiments, R⁴⁸ isindependently unsubstituted C₁-C₄ alkyl. In embodiments, R⁴⁸ isindependently unsubstituted 2 to 4 membered heteroalkyl. In embodiments,R⁴⁸ is independently unsubstituted C₃-C₆ cycloalkyl. In embodiments, R⁴⁸is independently unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R⁴⁸ is independently unsubstituted phenyl. In embodiments,R⁴⁸ is independently unsubstituted 5 to 6 membered heteroaryl.

In embodiments, R¹¹ is independently hydrogen, halogen, —CF₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCF₃, —OCHF₂, R⁵⁰-substituted or unsubstituted alkyl, R⁵⁰-substitutedor unsubstituted heteroalkyl, R⁵⁰-substituted or unsubstitutedcycloalkyl, R⁵⁰-substituted or unsubstituted heterocycloalkyl,R⁵⁰-substituted or unsubstituted aryl, or R⁵⁰-substituted orunsubstituted heteroaryl.

In embodiments, R¹¹ is independently hydrogen, —CF₃, —CN, —COOH, —CONH₂,R⁵⁰-substituted or unsubstituted alkyl, R⁵⁰-substituted or unsubstitutedheteroalkyl, R⁵⁰-substituted or unsubstituted cycloalkyl,R⁵⁰-substituted or unsubstituted heterocycloalkyl, R⁵⁰-substituted orunsubstituted aryl, or R⁵⁰-substituted or unsubstituted heteroaryl. Inembodiments, R¹¹ is independently an R⁵⁰-substituted or unsubstitutedC₁-C₄ alkyl, R⁵⁰-substituted or unsubstituted 2 to 4 memberedheteroalkyl, R⁵⁰-substituted or unsubstituted C₃-C₆ cycloalkyl,R⁵⁰-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R⁵⁰-substituted or unsubstituted phenyl, or R⁵⁰-substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R¹¹ isindependently an unsubstituted C₁-C₄ alkyl, unsubstituted 2 to 4membered heteroalkyl, unsubstituted C₃-C₆ cycloalkyl, unsubstituted 3 to6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to6 membered heteroaryl. In embodiments, R¹¹ is independently anunsubstituted C₁-C₄ alkyl. In embodiments, R¹¹ is independently anunsubstituted methyl. In embodiments, R¹¹ is independently anunsubstituted ethyl. In embodiments, R¹¹ is independently anunsubstituted isopropyl. In embodiments, R¹¹ is independently anunsubstituted tert-butyl. In embodiments, R¹¹ is independently hydrogen.In embodiments, R¹¹ is independently an R⁵⁰-substituted or unsubstitutedC₁-C₄ alkyl. In embodiments, R¹¹ is independently an R⁵⁰-substituted orunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R¹¹ isindependently an R⁵⁰-substituted or unsubstituted C₃-C₆ cycloalkyl. Inembodiments, R¹¹ is independently an R⁵⁰-substituted or unsubstituted 3to 6 membered heterocycloalkyl. In embodiments, R¹¹ is independently anR⁵⁰-substituted or unsubstituted phenyl. In embodiments, R¹¹ isindependently an R⁵⁰-substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R¹¹ is independently an unsubstituted C₁-C₄alkyl. In embodiments, R¹¹ is independently an unsubstituted 2 to 4membered heteroalkyl. In embodiments, R¹¹ is independently anunsubstituted C₃-C₆ cycloalkyl. In embodiments, R¹¹ is independently anunsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R¹¹ isindependently an unsubstituted phenyl. In embodiments, R¹¹ isindependently an unsubstituted 5 to 6 membered heteroaryl.

R⁵⁰ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁵¹-substituted or unsubstituted alkyl, R⁵¹-substituted or unsubstitutedheteroalkyl, R⁵¹-substituted or unsubstituted cycloalkyl,R⁵¹-substituted or unsubstituted heterocycloalkyl, R⁵¹-substituted orunsubstituted aryl, or R⁵¹-substituted or unsubstituted heteroaryl.

R⁵¹ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁵²-substituted or unsubstituted alkyl, R⁵²-substituted or unsubstitutedheteroalkyl, R⁵²-substituted or unsubstituted cycloalkyl,R⁵²-substituted or unsubstituted heterocycloalkyl, R⁵²-substituted orunsubstituted aryl, or R⁵²-substituted or unsubstituted heteroaryl.

In embodiments, R¹² is independently hydrogen, halogen, —CF₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCF₃, —OCHF₂, R⁵³-substituted or unsubstituted alkyl, R⁵³-substitutedor unsubstituted heteroalkyl, R⁵³-substituted or unsubstitutedcycloalkyl, R⁵³-substituted or unsubstituted heterocycloalkyl,R⁵³-substituted or unsubstituted aryl, or R⁵³-substituted orunsubstituted heteroaryl.

In embodiments, R¹² is independently hydrogen, —CF₃, —CN, —COOH, —CONH₂,R⁵³-substituted or unsubstituted alkyl, R⁵³-substituted or unsubstitutedheteroalkyl, R⁵³-substituted or unsubstituted cycloalkyl,R⁵³-substituted or unsubstituted heterocycloalkyl, R⁵³-substituted orunsubstituted aryl, or R⁵³-substituted or unsubstituted heteroaryl. Inembodiments, R¹² is independently an R⁵³-substituted or unsubstitutedC₁-C₄ alkyl, R⁵³-substituted or unsubstituted 2 to 4 memberedheteroalkyl, R⁵³-substituted or unsubstituted C₃-C₆ cycloalkyl,R⁵³-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R⁵³-substituted or unsubstituted phenyl, or R³-substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R¹² isindependently an unsubstituted C₁-C₄ alkyl, unsubstituted 2 to 4membered heteroalkyl, unsubstituted C₃-C₆ cycloalkyl, unsubstituted 3 to6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to6 membered heteroaryl. In embodiments, R¹² is independently anunsubstituted C₁-C₄ alkyl. In embodiments, R¹² is independently anunsubstituted methyl. In embodiments, R¹² is independently anunsubstituted ethyl. In embodiments, R¹² is independently anunsubstituted isopropyl. In embodiments, R¹² is independently anunsubstituted tert-butyl. In embodiments, R¹² is independently hydrogen.In embodiments, R¹² is independently an R⁵³-substituted or unsubstitutedC₁-C₄ alkyl. In embodiments, R¹² is independently an R⁵³-substituted orunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R¹² isindependently an R⁵³-substituted or unsubstituted C₃-C₆ cycloalkyl. Inembodiments, R¹² is independently an R⁵³-substituted or unsubstituted 3to 6 membered heterocycloalkyl. In embodiments, R¹² is independently anR⁵³-substituted or unsubstituted phenyl. In embodiments, R¹² isindependently an R⁵³-substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R¹² is independently an unsubstituted C₁-C₄alkyl. In embodiments, R¹² is independently an unsubstituted 2 to 4membered heteroalkyl. In embodiments, R¹² is independently anunsubstituted C₃-C₆ cycloalkyl. In embodiments, R¹² is independently anunsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R¹² isindependently an unsubstituted phenyl. In embodiments, R¹² isindependently an unsubstituted 5 to 6 membered heteroaryl.

R⁵³ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁵⁴-substituted or unsubstituted alkyl, R⁵⁴-substituted or unsubstitutedheteroalkyl, R⁵⁴-substituted or unsubstituted cycloalkyl,R⁵⁴-substituted or unsubstituted heterocycloalkyl, R⁵⁴-substituted orunsubstituted aryl, or R⁵⁴-substituted or unsubstituted heteroaryl.

R⁵⁴ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁵⁵-substituted or unsubstituted alkyl, R⁵⁵-substituted or unsubstitutedheteroalkyl, R⁵⁵-substituted or unsubstituted cycloalkyl,R⁵⁵-substituted or unsubstituted heterocycloalkyl, R⁵⁵-substituted orunsubstituted aryl, or R⁵⁵-substituted or unsubstituted heteroaryl.

In embodiments, R¹³ is independently hydrogen, halogen, —CF₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCF₃, —OCHF₂, R⁵⁶-substituted or unsubstituted alkyl, R⁵⁶-substitutedor unsubstituted heteroalkyl, R⁵⁶-substituted or unsubstitutedcycloalkyl, R⁵⁶-substituted or unsubstituted heterocycloalkyl,R⁵⁶-substituted or unsubstituted aryl, or R⁵⁶-substituted orunsubstituted heteroaryl.

In embodiments, R¹³ is independently hydrogen, —CF₃, —CN, —COOH, —CONH₂,R⁵⁶-substituted or unsubstituted alkyl, R⁵⁶-substituted or unsubstitutedheteroalkyl, R⁵⁶-substituted or unsubstituted cycloalkyl,R⁵⁶-substituted or unsubstituted heterocycloalkyl, R⁵⁶-substituted orunsubstituted aryl, or R⁵⁶-substituted or unsubstituted heteroaryl. Inembodiments, R¹³ is independently an R⁵⁶-substituted or unsubstitutedC₁-C₄ alkyl, R⁵⁶-substituted or unsubstituted 2 to 4 memberedheteroalkyl, R⁵⁶-substituted or unsubstituted C₃-C₆ cycloalkyl,R⁵⁶-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R⁵⁶-substituted or unsubstituted phenyl, or R⁵⁶-substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R¹³ isindependently an unsubstituted C₁-C₄ alkyl, unsubstituted 2 to 4membered heteroalkyl, unsubstituted C₃-C₆ cycloalkyl, unsubstituted 3 to6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to6 membered heteroaryl. In embodiments, R¹³ is independently anunsubstituted C₁-C₄ alkyl. In embodiments, R¹³ is independently anunsubstituted methyl. In embodiments, R¹³ is independently anunsubstituted ethyl. In embodiments, R¹³ is independently anunsubstituted isopropyl. In embodiments, R¹³ is independently anunsubstituted tert-butyl. In embodiments, R¹³ is independently hydrogen.In embodiments, R¹³ is independently an R⁵⁶-substituted or unsubstitutedC₁-C₄ alkyl. In embodiments, R¹³ is independently an R⁵⁶-substituted orunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R¹³ isindependently an R⁵⁶-substituted or unsubstituted C₃-C₆ cycloalkyl. Inembodiments, R¹³ is independently an R⁵⁶-substituted or unsubstituted 3to 6 membered heterocycloalkyl. In embodiments, R¹³ is independently anR⁵⁶-substituted or unsubstituted phenyl. In embodiments, R¹³ isindependently an R⁵⁶-substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R¹³ is independently an unsubstituted C₁-C₄alkyl. In embodiments, R¹³ is independently an unsubstituted 2 to 4membered heteroalkyl. In embodiments, R¹³ is independently anunsubstituted C₃-C₆ cycloalkyl. In embodiments, R¹³ is independently anunsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, R¹³ isindependently an unsubstituted phenyl. In embodiments, R¹³ isindependently an unsubstituted 5 to 6 membered heteroaryl.

R⁵⁶ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁵⁷-substituted or unsubstituted alkyl, R⁵⁷-substituted or unsubstitutedheteroalkyl, R⁵⁷-substituted or unsubstituted cycloalkyl,R⁵⁷-substituted or unsubstituted heterocycloalkyl, R⁵⁷-substituted orunsubstituted aryl, or R⁵⁷-substituted or unsubstituted heteroaryl.

R⁵⁷ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R⁵⁸-substituted or unsubstituted alkyl, R⁵⁸-substituted or unsubstitutedheteroalkyl, R⁵⁸-substituted or unsubstituted cycloalkyl,R⁵⁸-substituted or unsubstituted heterocycloalkyl, R⁵⁸-substituted orunsubstituted aryl, or R⁵⁸-substituted or unsubstituted heteroaryl.

In embodiments, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², and R¹³ are independentlyhydrogen. In embodiments, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², and R¹³ areindependently hydrogen, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCHF₂. Inembodiments, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², and R¹³ are independentlyhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. Inembodiments, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², and R¹³ are independentlyhydrogen, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCHF₂, substituted orunsubstituted C₁-C₂₀ alkyl, substituted or unsubstituted 2 to 20membered heteroalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted 3 to 8 membered heterocycloalkyl,substituted or unsubstituted C₆-C₁₀ aryl, or substituted orunsubstituted 5 to 10 membered heteroaryl. In embodiments, R⁷, R⁸, R⁹,R¹⁰, R¹¹, R¹², and R¹³ are independently hydrogen, halogen, —CF₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH,—OCF₃, —OCHF₂, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstitutedC₃-C₇ cycloalkyl, substituted or unsubstituted 3 to 7 memberedheterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, orsubstituted or unsubstituted 5 to 9 membered heteroaryl. In embodiments,R¹, R¹², and R¹³ are independently hydrogen. In embodiments, R¹¹, R¹²,and R¹³ are independently hydrogen, substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted 2 to 8 membered heteroalkyl,substituted or unsubstituted C₃-C₇ cycloalkyl, substituted orunsubstituted 3 to 7 membered heterocycloalkyl, substituted orunsubstituted C₆-C₁₀ aryl, or substituted or unsubstituted 5 to 9membered heteroaryl. In embodiments, R¹¹, R¹², and R¹³ are independentlyhydrogen, unsubstituted C₁-C₈ alkyl, unsubstituted 2 to 8 memberedheteroalkyl, unsubstituted C₃-C₇ cycloalkyl, unsubstituted 3 to 7membered heterocycloalkyl, unsubstituted C₆-C₁₀ aryl, or unsubstituted 5to 9 membered heteroaryl.

In embodiments, L¹ is a bond, —NH—, —NR²³—, —S—, —O—, substituted orunsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene. In embodiments, L¹ issubstituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, or substituted or unsubstituted heteroarylene. In embodiments,L¹ is L²-L³-L⁴-L⁵. L² is connected directly to a monovalent rapamycin ora monovalent rapamycin analog. L² is a bond, —NH—, —NR²⁶—, —S—, —O—,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, or substituted or unsubstituted heteroarylene. L³ is a bond,—NH—, —NR²⁹—, —S—, —O—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene. L⁴ is a bond, —NH—, —NR³²—,—S—, —O—, substituted or unsubstituted alkylene, substituted orunsubstituted heteroalkylene, substituted or unsubstitutedcycloalkylene, substituted or unsubstituted heterocycloalkylene,substituted or unsubstituted arylene, or substituted or unsubstitutedheteroarylene. L⁵ is a bond, —NH—, —NR³⁵—, —S—, —O—, substituted orunsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene. In embodiments, L² issubstituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, or substituted or unsubstituted heteroarylene. In embodiments,L³ is a bond, substituted or unsubstituted alkylene, substituted orunsubstituted heteroalkylene, substituted or unsubstitutedcycloalkylene, substituted or unsubstituted heterocycloalkylene,substituted or unsubstituted arylene, or substituted or unsubstitutedheteroarylene. In embodiments, L⁴ is a bond, substituted orunsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene. In embodiments, L⁵ is abond, substituted or unsubstituted alkylene, substituted orunsubstituted heteroalkylene, substituted or unsubstitutedcycloalkylene, substituted or unsubstituted heterocycloalkylene,substituted or unsubstituted arylene, or substituted or unsubstitutedheteroarylene. In embodiments, L¹ is a divalent linker including one ormore amino acids. In embodiments, L¹ is a divalent linker consisting ofamino acids. In embodiments, L¹ is a divalent linker including an aminoacid analog. In embodiments, L¹ is a divalent linker including an aminoacid mimetic. In embodiments, L¹ is a divalent linker consisting ofamino acid analogs. In embodiments, L¹ is a divalent linker consistingof amino acid mimetics.

In embodiments, L² is substituted or unsubstituted C₁-C₂₀ alkylene,substituted or unsubstituted 2 to 20 membered heteroalkylene,substituted or unsubstituted C₃-C₈ cycloalkylene, substituted orunsubstituted 3 to 8 membered heterocycloalkylene, substituted orunsubstituted C₆-C₁₀ arylene, or substituted or unsubstituted 5 to 10membered heteroarylene. In embodiments, L² is substituted orunsubstituted 3 to 8 membered heteroalkylene. In embodiments, L² is—CH₂CH₂OCH₂—. In embodiments, L² is unsubstituted 3 to 8 memberedheteroalkylene. In embodiments, L² is unsubstituted 3 to 6 memberedheteroalkylene. In embodiments, L² is unsubstituted 3 to 5 memberedheteroalkylene. In embodiments, L² is a divalent linker including one ormore amino acids. In embodiments, L² is a divalent linker consisting ofamino acids. In embodiments, L² is a divalent linker including an aminoacid analog. In embodiments, L² is a divalent linker including an aminoacid mimetic. In embodiments, L² is a divalent linker consisting ofamino acid analogs. In embodiments, L² is a divalent linker consistingof amino acid mimetics.

In embodiments, L³ is a bond, substituted or unsubstituted C₁-C₂₀alkylene, substituted or unsubstituted 2 to 20 membered heteroalkylene,substituted or unsubstituted C₃-C₈ cycloalkylene, substituted orunsubstituted 3 to 8 membered heterocycloalkylene, substituted orunsubstituted C₆-C₁₀ arylene, or substituted or unsubstituted 5 to 10membered heteroarylene. In embodiments, L³ is a substituted orunsubstituted 5 to 10 membered heteroarylene. In embodiments, L³ is abond. In embodiments, L³ is a substituted or unsubstituted 5 to 6membered heteroarylene. In embodiments, L³ is a unsubstituted 5 to 6membered heteroarylene. In embodiments, L³ is unsubstituted divalenttriazole. In embodiments, L³ is unsubstituted divalent1H-1,2,3-triazole. In embodiments, L³ is unsubstituted divalent2H-1,2,3-triazole. In embodiments, L³ is a divalent linker including oneor more amino acids. In embodiments, L³ is a divalent linker consistingof amino acids. In embodiments, L³ is a divalent linker including anamino acid analog. In embodiments, L³ is a divalent linker including anamino acid mimetic. In embodiments, L³ is a divalent linker consistingof amino acid analogs. In embodiments, L³ is a divalent linkerconsisting of amino acid mimetics.

In embodiments, L⁴ is a bond, substituted or unsubstituted C₁-C₂₀alkylene, substituted or unsubstituted 2 to 20 membered heteroalkylene,substituted or unsubstituted C₃-C₈ cycloalkylene, substituted orunsubstituted 3 to 8 membered heterocycloalkylene, substituted orunsubstituted C₆-C₁₀ arylene, or substituted or unsubstituted 5 to 10membered heteroarylene. In embodiments, L⁴ is a substituted orunsubstituted 2 to 12 membered heteroalkylene. In embodiments, L⁴ is asubstituted or unsubstituted 2 to 32 membered heteroalkylene. Inembodiments, L⁴ is a bond. In embodiments, L⁴ is a divalent linkerincluding one or more amino acids. In embodiments, L⁴ is a divalentlinker consisting of amino acids. In embodiments, L⁴ is a divalentlinker including an amino acid analog. In embodiments, L⁴ is a divalentlinker including an amino acid mimetic. In embodiments, L⁴ is a divalentlinker consisting of amino acid analogs. In embodiments, L⁴ is adivalent linker consisting of amino acid mimetics.

In embodiments, L⁵ is a bond, substituted or unsubstituted C₁-C₂₀alkylene, substituted or unsubstituted 2 to 20 membered heteroalkylene,substituted or unsubstituted C₃-C₈ cycloalkylene, substituted orunsubstituted 3 to 8 membered heterocycloalkylene, substituted orunsubstituted C₆-C₁₀ arylene, or substituted or unsubstituted 5 to 10membered heteroarylene. In embodiments, L⁵ is a substituted orunsubstituted 2 to 12 membered heteroalkylene. In embodiments, L⁵ is asubstituted or unsubstituted 2 to 32 membered heteroalkylene. Inembodiments, L⁵ is a bond. In embodiments, L⁵ is a divalent linkerincluding one or more amino acids. In embodiments, L⁵ is a divalentlinker consisting of amino acids. In embodiments, L⁵ is a divalentlinker including an amino acid analog. In embodiments, L⁵ is a divalentlinker including an amino acid mimetic. In embodiments, L⁵ is a divalentlinker consisting of amino acid analogs. In embodiments, L⁵ is adivalent linker consisting of amino acid mimetics.

In embodiments, L¹ is a divalent oligomer of ethylene oxide. Inembodiments, L⁵ is a divalent polyethylene glycol. In embodiments, L⁵ isa divalent oligomer of ethylene oxide having 2 to 30 linear atoms(carbon and oxygen) between the two termini connecting to the remainderof the compound. In embodiments, L⁵ is a —(CH₂)₄C(O)NH—. In embodiments,L⁵ is a 2 to 8 membered substituted heteroalkylene. In embodiments, L⁵is a 3 to 6 membered substituted heteroalkylene. In embodiments, L⁵ is a5 to 6 membered substituted heteroalkylene. In embodiments, L⁵ is a 5 to7 membered oxo substituted heteroalkylene. In embodiments, L⁵ is anunsubstituted C₁-C₆ alkylene.

In embodiments, L⁴ is a divalent oligomer of ethylene oxide. Inembodiments, L⁴ is a divalent polyethylene glycol. In embodiments, L⁴ isa divalent oligomer of ethylene oxide having 2 to 30 linear atoms(carbon and oxygen) between the two termini connecting to the remainderof the compound. In embodiments, L⁴ is —(CH₂CH₂O)_(b)CH₂CH₂— and b is aninteger from 1 to 16. In embodiments, L⁴ is —(CH₂CH₂O)_(b)CH₂— and b isan integer from 1 to 16. In embodiments, L⁴ is —(CH₂CH₂O)_(b)— and b isan integer from 1 to 16. In embodiments, b is an integer from 2 to 15.In embodiments, b is an integer from 3 to 14. In embodiments, b is aninteger from 4 to 12. In embodiments, b is an integer from 5 to 10. Inembodiments, b is an integer from 5 to 8. In embodiments, b is aninteger from 6 to 7.

In embodiments, L⁴-L⁵ is a 2 to 36 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 2 to 34 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 2 to 32 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 2 to 30 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 2 to 28 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 2 to 24 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 2 to 30 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 2 to 22 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 2 to 20 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 2 to 18 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 2 to 16 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 2 to 14 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 2 to 12 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 4 to 36 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 6 to 36 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 8 to 36 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 10 to 36 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 12 to 36 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 14 to 36 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 16 to 36 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 18 to 36 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 20 to 36 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 22 to 36 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 24 to 36 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 4 to 32 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 4 to 28 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 8 to 26 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 12 to 26 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 16 to 26 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 20 to 26 membered substituted heteroalkylene.In embodiments, L⁴-L⁵ is a 22 to 26 membered substituted heteroalkylene.

In embodiments, the linker is formed by a conjugation or bioconjugationreaction combining a first reactant moiety covalently bonded to therapamycin or rapamycin analog and a second reactant moiety covalentlybonded to the active site mTOR inhibitor. In such embodiments, thecompound formed by such conjugation or bioconjugation reaction(including compounds as described herein) may be referred to as aconjugate.

In some embodiments, L¹ is L²-L³-L⁴-L⁵; L² is —CH₂CH₂OCH₂—; L³ is 5 to10 membered heteroarylene; L⁴ is —(CH₂CH₂O)_(b)—; b is an integer from 2to 8; L⁵ is —CH₂CH₂C═(O)NH(CH₂)_(b10)—; and b10 is an integer from 1 to6. In some embodiments, L¹ is L²-L³-L⁴-L⁵; L² is 2 to 8 memberedheteroalkylene comprising at least one NH or O; L³ is 5 to 10 memberedheteroarylene; L⁴ is —[(CH₂)_(b11)O]_(b12)—; b11 is an integer from 1 to3; b12 is an integer from 1 to 8; L⁵ is —CH₂CH₂C═(O)NH(CH₂)_(b10); andb10 is an integer from 1 to 6. In some embodiments, L¹ is L²-L³-L⁴-L⁵;L² is —CH₂CH₂OCH₂—; L³ is 5 membered heteroarylene; L⁴ is—(CH₂CH₂O)_(b)—; b is an integer from 4 to 8; and L⁵ is—CH₂CH₂C═(O)NH(CH₂)₄. In some embodiments, L¹ is L²-L³-L⁴-L⁵; L² is—CH₂CH₂OCH₂—; L³ is triazolylene; L⁴ is —(CH₂CH₂O)_(b)—; b is an integerfrom 4 to 8; and L⁵ is —CH₂CH₂C═(O)NH(CH₂)₄. In some embodiments, L¹ isL²-L³-L⁴-L⁵; L² is —CH₂CH₂OCH₂—; L³ is 5 to 10 membered heteroarylene;L⁴ is —(CH₂)_(b)—; b is an integer from 2 to 8; and L⁵ is a bond.

Conjugates described herein may be synthesized using bioconjugate orconjugate chemistry. Conjugate chemistry includes coupling two moleculestogether to form an adduct. Conjugation may be a covalent modification.Currently favored classes of conjugate chemistry reactions availablewith reactive known reactive groups are those which proceed underrelatively mild conditions. These include, but are not limited tonucleophilic substitutions (e.g., reactions of amines and alcohols withacyl halides, active esters), electrophilic substitutions (e.g., enaminereactions) and additions to carbon-carbon and carbon-heteroatom multiplebonds (e.g., Michael reaction, Diels-Alder addition). These and otheruseful reactions are discussed in, for example, March, ADVANCED ORGANICCHEMISTRY, 3rd Ed., John Wiley & Sons, New York, 1985; Hermanson,BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney etal., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol. 198,American Chemical Society, Washington, D.C., 1982. In embodiments, thebioconjugation reaction is a click chemistry reaction (Angewandte ChemieInternational Edition 40 (11): 2004-2021). In embodiments, thebioconjugation reaction is a Huisgen cyclization of azides. Inembodiments, the bioconjugation reaction is a copper catalyzed Huisgencyclization of azides.

Useful reactive functional groups used for conjugate chemistries hereininclude, for example:

-   -   (a) carboxyl groups and various derivatives thereof including,        but not limited to, N-hydroxysuccinimide esters,        N-hydroxybenztriazole esters, acid halides, acyl imidazoles,        thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and        aromatic esters;    -   (b) hydroxyl groups which can be converted to esters, ethers,        aldehydes, etc.    -   (c) haloalkyl groups wherein the halide can be later displaced        with a nucleophilic group such as, for example, an amine, a        carboxylate anion, thiol anion, carbanion, or an alkoxide ion,        thereby resulting in the covalent attachment of a new group at        the site of the halogen atom;    -   (d) dienophile groups which are capable of participating in        Diels-Alder reactions such as, for example, maleimido groups;    -   (e) aldehyde or ketone groups such that subsequent        derivatization is possible via formation of carbonyl derivatives        such as, for example, imines, hydrazones, semicarbazones or        oximes, or via such mechanisms as Grignard addition or        alkyllithium addition;    -   (f) sulfonyl halide groups for subsequent reaction with amines,        for example, to form sulfonamides;    -   (g) thiol groups, which can be converted to disulfides, reacted        with acyl halides, or bonded to metals such as gold;    -   (h) amine or sulfhydryl groups, which can be, for example,        acylated, alkylated or oxidized;    -   (i) alkenes, which can undergo, for example, cycloadditions,        acylation, Michael addition, etc;    -   (j) epoxides, which can react with, for example, amines and        hydroxyl compounds;    -   (k) phosphoramidites and other standard functional groups useful        in nucleic acid synthesis;    -   (l) metal silicon oxide bonding; and    -   (m) metal bonding to reactive phosphorus groups (e.g.        phosphines) to form, for example, phosphate diester bonds.    -   (n) azides coupled to alkynes using copper catalyzed        cycloaddition click chemistry.

The reactive functional groups can be chosen such that they do notparticipate in, or interfere with, the chemical stability of theconjugate described herein. Alternatively, a reactive functional groupcan be protected from participating in the crosslinking reaction by thepresence of a protecting group.

In some embodiments of the compounds provided herein, L¹ isindependently R²³-substituted or unsubstituted alkylene, R²³-substitutedor unsubstituted heteroalkylene, R²³-substituted or unsubstitutedcycloalkylene, R²³-substituted or unsubstituted heterocycloalkylene,R²³-substituted or unsubstituted arylene, or R²³-substituted orunsubstituted heteroarylene.

In embodiments, L¹ is a bond, —NH—, —NR²³—, —S—, —O—, —C(O)—, —NHC(O)—,—C(O)NH—, —NHC(O)NH—, —NHC(NH)NH—, —C(S)—, R²³-substituted orunsubstituted C₁-C₂₀ alkylene, R²³-substituted or unsubstituted 2 to 20membered heteroalkylene, R²³-substituted or unsubstituted C₃-C₈cycloalkylene, R²³-substituted or unsubstituted 3 to 8 memberedheterocycloalkylene, R²³-substituted or unsubstituted C₆-C₁₀ arylene, orR²³-substituted or unsubstituted 5 to 10 membered heteroarylene. Inembodiments, L¹ is a bond. In embodiments, L¹ is —NH—. In embodiments,L¹ is —NR²³—. In embodiments, L¹ is —S—. In embodiments, L¹ is —O—. Inembodiments, L¹ is —C(O)—. In embodiments, L¹ is —NHC(O)—. Inembodiments, L¹ is —C(O)NH—. In embodiments, L¹ is —NHC(O)NH—. Inembodiments, L¹ is —NHC(NH)NH—. In embodiments, L¹ is —C(S)—. Inembodiments, L¹ is R²³-substituted or unsubstituted C₁-C₂₀ alkylene. Inembodiments, L¹ is R²³-substituted or unsubstituted 2 to 20 memberedheteroalkylene. In embodiments, L¹ is R²³-substituted or unsubstitutedC₃-C₈ cycloalkylene. In embodiments, L¹ is R²³-substituted orunsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, L¹ isR²³-substituted or unsubstituted C₆-C₁₀ arylene. In embodiments, L¹ isR²³-substituted or unsubstituted 5 to 10 membered heteroarylene. Inembodiments, L¹ is R²³-substituted C₁-C₂₀ alkylene. In embodiments, L¹is R²³-substituted 2 to 20 membered heteroalkylene. In embodiments, L¹is R²³-substituted C₃-C₈ cycloalkylene. In embodiments, L¹ isR²³-substituted 3 to 8 membered heterocycloalkylene. In embodiments, L¹is R²³-substituted C₆-C₁₀ arylene. In embodiments, L¹ is R²³-substituted5 to 10 membered heteroarylene. In embodiments, L¹ is unsubstitutedC₁-C₂₀ alkylene. In embodiments, L¹ is unsubstituted 2 to 20 memberedheteroalkylene. In embodiments, L¹ is unsubstituted C₃-C₈ cycloalkylene.In embodiments, L¹ is unsubstituted 3 to 8 membered heterocycloalkylene.In embodiments, L¹ is unsubstituted C₆-C₁₀ arylene. In embodiments, L¹is unsubstituted 5 to 10 membered heteroarylene. In embodiments, L¹ isR²³-substituted C₁-C₁₅ alkylene. In embodiments, L¹ is R²³-substituted 2to 15 membered heteroalkylene. In embodiments, L¹ is R²³-substitutedC₃-C₆ cycloalkylene. In embodiments, L¹ is R²³-substituted 3 to 6membered heterocycloalkylene. In embodiments, L¹ is R²³-substitutedphenylene. In embodiments, L¹ is R²³-substituted 5 to 6 memberedheteroarylene. In embodiments, L¹ is unsubstituted C₁-C₁₅ alkylene. Inembodiments, L¹ is unsubstituted 2 to 15 membered heteroalkylene. Inembodiments, L¹ is unsubstituted C₃-C₆ cycloalkylene. In embodiments, L¹is unsubstituted 3 to 6 membered heterocycloalkylene. In embodiments, L¹is unsubstituted phenylene. In embodiments, L¹ is unsubstituted 5 to 6membered heteroarylene. In embodiments, L¹ is R²³-substituted C₁-C₁₀alkylene. In embodiments, L¹ is R²³-substituted 2 to 10 memberedheteroalkylene. In embodiments, L¹ is R²³-substituted C₄-C₆cycloalkylene. In embodiments, L¹ is R²³-substituted 4 to 6 memberedheterocycloalkylene. In embodiments, L¹ is R²³-substituted phenylene. Inembodiments, L¹ is R²³-substituted 5 membered heteroarylene. Inembodiments, L¹ is R²³-substituted C₁-C₈ alkylene. In embodiments, L¹ isR²³-substituted 2 to 8 membered heteroalkylene. In embodiments, L¹ isR²³-substituted C₅-C₆ cycloalkylene. In embodiments, L¹ isR²³-substituted 5 to 6 membered heterocycloalkylene. In embodiments, L¹is R²³-substituted 6 membered heteroarylene. In embodiments, L¹ isR²³-substituted C₁-C₆ alkylene. In embodiments, L¹ is R²³-substituted 2to 6 membered heteroalkylene. In embodiments, L¹ is R²³-substitutedC₆-C₂₀ alkylene. In embodiments, L¹ is R²³-substituted 6 to 20 memberedheteroalkylene. In embodiments, L¹ is unsubstituted C₁-C₁₀ alkylene. Inembodiments, L¹ is unsubstituted 2 to 10 membered heteroalkylene. Inembodiments, L¹ is unsubstituted C₄-C₆ cycloalkylene. In embodiments, L¹is unsubstituted 4 to 6 membered heterocycloalkylene. In embodiments, L¹is unsubstituted phenylene. In embodiments, L¹ is unsubstituted 5membered heteroarylene. In embodiments, L¹ is unsubstituted C₁-C₈alkylene. In embodiments, L¹ is unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L¹ is unsubstituted C₅-C₆ cycloalkylene.In embodiments, L¹ is unsubstituted 5 to 6 membered heterocycloalkylene.In embodiments, L¹ is unsubstituted 6 membered heteroarylene. Inembodiments, L¹ is unsubstituted C₁-C₆ alkylene. In embodiments, L¹ isunsubstituted 2 to 6 membered heteroalkylene. In embodiments, L¹ isunsubstituted C₆-C₂₀ alkylene. In embodiments, L¹ is unsubstituted 6 to20 membered heteroalkylene.

R²³ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R²⁴-substituted or unsubstituted alkyl, R²⁴-substituted or unsubstitutedheteroalkyl, R²⁴-substituted or unsubstituted cycloalkyl,R²⁴-substituted or unsubstituted heterocycloalkyl, R²⁴-substituted orunsubstituted aryl, or R²⁴-substituted or unsubstituted heteroaryl.

In embodiments, R²³ is independently —NH₂. In embodiments, R²³ isindependently —OH. In embodiments, R²³ is independently halogen. Inembodiments, R²³ is independently —CN. In embodiments, R²³ isindependently oxo. In embodiments, R²³ is independently —CF₃. Inembodiments, R²³ is independently —COOH. In embodiments, R²³ isindependently —CONH₂. In embodiments, R²³ is independently —NO₂. Inembodiments, R²³ is independently —SH. In embodiments, R²³ isindependently —SO₃H. In embodiments, R²³ is independently —SO₄H. Inembodiments, R²³ is independently —SO₂NH₂. In embodiments, R²³ isindependently —NHNH₂. In embodiments, R²³ is independently —ONH₂. Inembodiments, R²³ is independently —NHC═(O)NHNH₂. In embodiments, R²³ isindependently —NHC═(O) NH₂. In embodiments, R²³ is independently—NHSO₂H. In embodiments, R²³ is independently —NHC═(O)H. In embodiments,R²³ is independently —NHC(O)—OH. In embodiments, R²³ is independently—NHOH. In embodiments, R²³ is independently —OCF₃. In embodiments, R²³is independently —OCHF₂. In embodiments, R²³ is independently —CCl₃. Inembodiments, R²³ is independently —CBr₃. In embodiments, R²³ isindependently —Cl₃. In embodiments, R²³ is independently —F. Inembodiments, R²³ is independently —Cl. In embodiments, R²³ isindependently —Br. In embodiments, R²³ is independently —I. Inembodiments, R²³ is independently R²⁴-substituted C₁-C₄ alkyl. Inembodiments, R²³ is independently R²⁴-substituted 2 to 4 memberedheteroalkyl. In embodiments, R²³ is independently R²⁴-substituted C₃-C₆cycloalkyl. In embodiments, R²³ is independently R²⁴-substituted 3 to 6membered heterocycloalkyl. In embodiments, R²³ is independentlyR²⁴-substituted phenyl. In embodiments, R²³ is independentlyR²⁴-substituted 5 to 6 membered heteroaryl. In embodiments, R²³ isindependently unsubstituted C₁-C₄ alkyl. In embodiments, R²³ isindependently unsubstituted 2 to 4 membered heteroalkyl. In embodiments,R²³ is independently unsubstituted C₃-C₆ cycloalkyl. In embodiments, R²³is independently unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R²³ is independently unsubstituted phenyl. In embodiments,R²³ is independently unsubstituted 5 to 6 membered heteroaryl.

R²⁴ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R²⁵-substituted or unsubstituted alkyl, R²⁵-substituted or unsubstitutedheteroalkyl, R²⁵-substituted or unsubstituted cycloalkyl,R²⁵-substituted or unsubstituted heterocycloalkyl, R²⁵-substituted orunsubstituted aryl, or R²⁵-substituted or unsubstituted heteroaryl.

In embodiments, R²⁴ is independently —NH₂. In embodiments, R²⁴ isindependently —OH. In embodiments, R²⁴ is independently halogen. Inembodiments, R²⁴ is independently —CN. In embodiments, R²⁴ isindependently oxo. In embodiments, R²⁴ is independently —CF₃. Inembodiments, R²⁴ is independently —COOH. In embodiments, R²⁴ isindependently —CONH₂. In embodiments, R²⁴ is independently —NO₂. Inembodiments, R²⁴ is independently —SH. In embodiments, R²⁴ isindependently —SO₃H. In embodiments, R²⁴ is independently —SO₄H. Inembodiments, R²⁴ is independently —SO₂NH₂. In embodiments, R²⁴ isindependently —NHNH₂. In embodiments, R²⁴ is independently —ONH₂. Inembodiments, R²⁴ is independently —NHC═(O)NHNH₂. In embodiments, R²⁴ isindependently —NHC═(O) NH₂. In embodiments, R²⁴ is independently—NHSO₂H. In embodiments, R²⁴ is independently —NHC═(O)H. In embodiments,R²⁴ is independently —NHC(O)—OH. In embodiments, R²⁴ is independently—NHOH. In embodiments, R²⁴ is independently —OCF₃. In embodiments, R²⁴is independently —OCHF₂. In embodiments, R²⁴ is independently —CCl₃. Inembodiments, R²⁴ is independently —CBr₃. In embodiments, R²⁴ isindependently —Cl₃. In embodiments, R²⁴ is independently —F. Inembodiments, R²⁴ is independently —Cl. In embodiments, R²⁴ isindependently —Br. In embodiments, R²⁴ is independently —I. Inembodiments, R²⁴ is independently R²⁵-substituted C₁-C₄ alkyl. Inembodiments, R²⁴ is independently R²⁵-substituted 2 to 4 memberedheteroalkyl. In embodiments, R²⁴ is independently R²⁵-substituted C₃-C₆cycloalkyl. In embodiments, R²⁴ is independently R²⁵-substituted 3 to 6membered heterocycloalkyl. In embodiments, R²⁴ is independentlyR²⁵-substituted phenyl. In embodiments, R²⁴ is independentlyR²⁵-substituted 5 to 6 membered heteroaryl. In embodiments, R²⁴ isindependently unsubstituted C₁-C₄ alkyl. In embodiments, R²⁴ isindependently unsubstituted 2 to 4 membered heteroalkyl. In embodiments,R²⁴ is independently unsubstituted C₃-C₆ cycloalkyl. In embodiments, R²⁴is independently unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R²⁴ is independently unsubstituted phenyl. In embodiments,R²⁴ is independently unsubstituted 5 to 6 membered heteroaryl.

In some embodiments of the compounds provided herein, L² isindependently a bond, R²⁶-substituted or unsubstituted alkylene,R²⁶-substituted or unsubstituted heteroalkylene, R²⁶-substituted orunsubstituted cycloalkylene, R²⁶-substituted or unsubstitutedheterocycloalkylene, R²⁶-substituted or unsubstituted arylene, orR²⁶-substituted or unsubstituted heteroarylene.

In embodiments, L² is a bond, —NH—, —NR²⁶—, —S—, —O—, —C(O)—, —NHC(O)—,—C(O)NH—, —NHC(O)NH—, —NHC(NH)NH—, —C(S)—, R²⁶-substituted orunsubstituted C₁-C₂₀ alkylene, R²⁶-substituted or unsubstituted 2 to 20membered heteroalkylene, R²⁶-substituted or unsubstituted C₃-C₈cycloalkylene, R²⁶-substituted or unsubstituted 3 to 8 memberedheterocycloalkylene, R²⁶-substituted or unsubstituted C₆-C₁₀ arylene, orR²⁶-substituted or unsubstituted 5 to 10 membered heteroarylene. Inembodiments, L² is a bond. In embodiments, L² is —NH—. In embodiments,L² is —NR²⁶—. In embodiments, L² is —S—. In embodiments, L² is —O—. Inembodiments, L² is —C(O)—. In embodiments, L² is —NHC(O)—. Inembodiments, L² is —C(O)NH—. In embodiments, L² is —NHC(O)NH—. Inembodiments, L² is —NHC(NH)NH—. In embodiments, L² is —C(S)—. Inembodiments, L² is R²⁶-substituted or unsubstituted C₁-C₂₀ alkylene. Inembodiments, L² is R²⁶-substituted or unsubstituted 2 to 20 memberedheteroalkylene. In embodiments, L² is R²⁶-substituted or unsubstitutedC₃-C₈ cycloalkylene. In embodiments, L² is R²⁶-substituted orunsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, L² isR²⁶-substituted or unsubstituted C₆-C₁₀ arylene. In embodiments, L² isR²⁶-substituted or unsubstituted 5 to 10 membered heteroarylene. Inembodiments, L² is R²⁶-substituted C₁-C₂₀ alkylene. In embodiments, L²is R²⁶-substituted 2 to 20 membered heteroalkylene. In embodiments, L²is R²⁶-substituted C₃-C₈ cycloalkylene. In embodiments, L² isR²⁶-substituted 3 to 8 membered heterocycloalkylene. In embodiments, L²is R²⁶-substituted C₆-C₁₀ arylene. In embodiments, L² is R²⁶-substituted5 to 10 membered heteroarylene. In embodiments, L² is unsubstitutedC₁-C₂₀ alkylene. In embodiments, L² is unsubstituted 2 to 20 memberedheteroalkylene. In embodiments, L² is unsubstituted C₃-C₈ cycloalkylene.In embodiments, L² is unsubstituted 3 to 8 membered heterocycloalkylene.In embodiments, L² is unsubstituted C₆-C₁₀ arylene. In embodiments, L²is unsubstituted 5 to 10 membered heteroarylene. In embodiments, L² isR²⁶-substituted C₁-C₁₅ alkylene. In embodiments, L² is R²⁶-substituted 2to 15 membered heteroalkylene. In embodiments, L² is R²⁶-substitutedC₃-C₆ cycloalkylene. In embodiments, L² is R²⁶-substituted 3 to 6membered heterocycloalkylene. In embodiments, L² is R²⁶-substitutedphenylene. In embodiments, L² is R²⁶-substituted 5 to 6 memberedheteroarylene. In embodiments, L² is unsubstituted C₁-C₁₅ alkylene. Inembodiments, L² is unsubstituted 2 to 15 membered heteroalkylene. Inembodiments, L² is unsubstituted C₃-C₆ cycloalkylene. In embodiments, L²is unsubstituted 3 to 6 membered heterocycloalkylene. In embodiments, L²is unsubstituted phenylene. In embodiments, L² is unsubstituted 5 to 6membered heteroarylene. In embodiments, L² is R²⁶-substituted C₁-C₁₀alkylene. In embodiments, L² is R²⁶-substituted 2 to 10 memberedheteroalkylene. In embodiments, L² is R²⁶-substituted C₄-C₆cycloalkylene. In embodiments, L² is R²⁶-substituted 4 to 6 memberedheterocycloalkylene. In embodiments, L² is R²⁶-substituted phenylene. Inembodiments, L² is R²⁶-substituted 5 membered heteroarylene. Inembodiments, L² is R²⁶-substituted C₁-C₈ alkylene. In embodiments, L² isR²⁶-substituted 2 to 8 membered heteroalkylene. In embodiments, L² isR²⁶-substituted C₅-C₆ cycloalkylene. In embodiments, L² isR²⁶-substituted 5 to 6 membered heterocycloalkylene. In embodiments, L²is R²⁶-substituted 6 membered heteroarylene. In embodiments, L² isR²⁶-substituted C₁-C₆ alkylene. In embodiments, L² is R^(2E)-substituted2 to 6 membered heteroalkylene. In embodiments, L² is R²⁶-substitutedC₆-C₂₀ alkylene. In embodiments, L² is R²⁶-substituted 6 to 20 memberedheteroalkylene. In embodiments, L² is unsubstituted C₁-C₁₀ alkylene. Inembodiments, L² is unsubstituted 2 to 10 membered heteroalkylene. Inembodiments, L² is unsubstituted C₄-C₆ cycloalkylene. In embodiments, L²is unsubstituted 4 to 6 membered heterocycloalkylene. In embodiments, L²is unsubstituted phenylene. In embodiments, L² is unsubstituted 5membered heteroarylene. In embodiments, L² is unsubstituted C₁-C₈alkylene. In embodiments, L² is unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L² is unsubstituted C₅-C₆ cycloalkylene.In embodiments, L² is unsubstituted 5 to 6 membered heterocycloalkylene.In embodiments, L² is unsubstituted 6 membered heteroarylene. Inembodiments, L² is unsubstituted C₁-C₆ alkylene. In embodiments, L² isunsubstituted 2 to 6 membered heteroalkylene. In embodiments, L² isunsubstituted C₆-C₂₀ alkylene. In embodiments, L² is unsubstituted 6 to20 membered heteroalkylene.

R²⁶ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R²⁷-substituted or unsubstituted alkyl, R²⁷-substituted or unsubstitutedheteroalkyl, R²⁷-substituted or unsubstituted cycloalkyl, R²⁷substituted or unsubstituted heterocycloalkyl, R²⁷-substituted orunsubstituted aryl, or R²⁷-substituted or unsubstituted heteroaryl.

In embodiments, R²⁶ is independently —NH₂. In embodiments, R²⁶ isindependently —OH. In embodiments, R²⁶ is independently halogen. Inembodiments, R²⁶ is independently —CN. In embodiments, R²⁶ isindependently oxo. In embodiments, R²⁶ is independently —CF₃. Inembodiments, R²⁶ is independently —COOH. In embodiments, R²⁶ isindependently —CONH₂. In embodiments, R²⁶ is independently —NO₂. Inembodiments, R²⁶ is independently —SH. In embodiments, R²⁶ isindependently —SO₃H. In embodiments, R²⁶ is independently —SO₄H. Inembodiments, R²⁶ is independently —SO₂NH₂. In embodiments, R²⁶ isindependently —NHNH₂. In embodiments, R²⁶ is independently —ONH₂. Inembodiments, R²⁶ is independently —NHC═(O)NHNH₂. In embodiments, R²⁶ isindependently —NHC═(O) NH₂. In embodiments, R²⁶ is independently—NHSO₂H. In embodiments, R²⁶ is independently —NHC═(O)H. In embodiments,R²⁶ is independently —NHC(O)—OH. In embodiments, R²⁶ is independently—NHOH. In embodiments, R²⁶ is independently —OCF₃. In embodiments, R²⁶is independently —OCHF₂. In embodiments, R²⁶ is independently —CCl₃. Inembodiments, R²⁶ is independently —CBr₃. In embodiments, R²⁶ isindependently —Cl₃. In embodiments, R²⁶ is independently —F. Inembodiments, R²⁶ is independently —Cl. In embodiments, R²⁶ isindependently —Br. In embodiments, R²⁶ is independently —I. Inembodiments, R²⁶ is independently R²⁷-substituted C₁-C₄ alkyl. Inembodiments, R²⁶ is independently R²⁷-substituted 2 to 4 memberedheteroalkyl. In embodiments, R²⁶ is independently R²⁷-substituted C₃-C₆cycloalkyl. In embodiments, R²⁶ is independently R²⁷-substituted 3 to 6membered heterocycloalkyl. In embodiments, R²⁶ is independentlyR²⁷-substituted phenyl. In embodiments, R²⁶ is independentlyR²⁷-substituted 5 to 6 membered heteroaryl. In embodiments, R²⁶ isindependently unsubstituted C₁-C₄ alkyl. In embodiments, R²⁶ isindependently unsubstituted 2 to 4 membered heteroalkyl. In embodiments,R²⁶ is independently unsubstituted C₃-C₆ cycloalkyl. In embodiments, R²⁶is independently unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R²⁶ is independently unsubstituted phenyl. In embodiments,R²⁶ is independently unsubstituted 5 to 6 membered heteroaryl.

R²⁷ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R²⁸-substituted or unsubstituted alkyl, R²⁸-substituted or unsubstitutedheteroalkyl, R²⁸-substituted or unsubstituted cycloalkyl,R²⁸-substituted or unsubstituted heterocycloalkyl, R²⁸-substituted orunsubstituted aryl, or R²⁸-substituted or unsubstituted heteroaryl.

In embodiments, R²⁷ is independently —NH₂. In embodiments, R²⁷ isindependently —OH. In embodiments, R²⁷ is independently halogen. Inembodiments, R²⁷ is independently —CN. In embodiments, R²⁷ isindependently oxo. In embodiments, R²⁷ is independently —CF₃. Inembodiments, R²⁷ is independently —COOH. In embodiments, R²⁷ isindependently —CONH₂. In embodiments, R²⁷ is independently —NO₂. Inembodiments, R²⁷ is independently —SH. In embodiments, R²⁷ isindependently —SO₃H. In embodiments, R²⁷ is independently —SO₄H. Inembodiments, R²⁷ is independently —SO₂NH₂. In embodiments, R²⁷ isindependently —NHNH₂. In embodiments, R²⁷ is independently —ONH₂. Inembodiments, R²⁷ is independently —NHC═(O)NHNH₂. In embodiments, R²⁷ isindependently —NHC═(O) NH₂. In embodiments, R²⁷ is independently—NHSO₂H. In embodiments, R²⁷ is independently —NHC═(O)H. In embodiments,R²⁷ is independently —NHC(O)—OH. In embodiments, R²⁷ is independently—NHOH. In embodiments, R²⁷ is independently —OCF₃. In embodiments, R²⁷is independently —OCHF₂. In embodiments, R²⁷ is independently —CCl₃. Inembodiments, R²⁷ is independently —CBr₃. In embodiments, R²⁷ isindependently —Cl₃. In embodiments, R²⁷ is independently —F. Inembodiments, R²⁷ is independently —Cl. In embodiments, R²⁷ isindependently —Br. In embodiments, R²⁷ is independently —I. Inembodiments, R²⁷ is independently R²⁸-substituted C₁-C₄ alkyl. Inembodiments, R²⁷ is independently R²⁸-substituted 2 to 4 memberedheteroalkyl. In embodiments, R²⁷ is independently R²⁸-substituted C₃-C₆cycloalkyl. In embodiments, R²⁷ is independently R²⁸-substituted 3 to 6membered heterocycloalkyl. In embodiments, R²⁷ is independentlyR²⁸-substituted phenyl. In embodiments, R²⁷ is independentlyR²⁸-substituted 5 to 6 membered heteroaryl. In embodiments, R²⁷ isindependently unsubstituted C₁-C₄ alkyl. In embodiments, R²⁷ isindependently unsubstituted 2 to 4 membered heteroalkyl. In embodiments,R²⁷ is independently unsubstituted C₃-C₆ cycloalkyl. In embodiments, R²⁷is independently unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R²⁷ is independently unsubstituted phenyl. In embodiments,R²⁷ is independently unsubstituted 5 to 6 membered heteroaryl.

In some embodiments of the compounds provided herein, L³ isindependently a bond, R²⁹-substituted or unsubstituted alkylene,R²⁹-substituted or unsubstituted heteroalkylene, R²⁹-substituted orunsubstituted cycloalkylene, R²⁹-substituted or unsubstitutedheterocycloalkylene, R²⁹-substituted or unsubstituted arylene, orR²⁹-substituted or unsubstituted heteroarylene.

In embodiments, L³ is a bond, —NH—, —NR²⁹—, —S—, —O—, —C(O)—, —NHC(O)—,—C(O)NH—, —NHC(O)NH—, —NHC(NH)NH—, —C(S)—, R²⁹-substituted orunsubstituted C₁-C₂₀ alkylene, R²⁹-substituted or unsubstituted 2 to 20membered heteroalkylene, R²⁹-substituted or unsubstituted C₃-C₈cycloalkylene, R²⁹-substituted or unsubstituted 3 to 8 memberedheterocycloalkylene, R²⁹-substituted or unsubstituted C₆-C₁₀ arylene, orR²⁹-substituted or unsubstituted 5 to 10 membered heteroarylene. Inembodiments, L³ is a bond. In embodiments, L³ is —NH—. In embodiments,L³ is —NR²⁹—. In embodiments, L³ is —S—. In embodiments, L³ is —O—. Inembodiments, L³ is —C(O)—. In embodiments, L³ is —NHC(O)—. Inembodiments, L³ is —C(O)NH—. In embodiments, L³ is —NHC(O)NH—. Inembodiments, L³ is —NHC(NH)NH—. In embodiments, L³ is —C(S)—. Inembodiments, L³ is R²⁹-substituted or unsubstituted C₁-C₂₀ alkylene. Inembodiments, L³ is R²⁹-substituted or unsubstituted 2 to 20 memberedheteroalkylene. In embodiments, L³ is R²⁹-substituted or unsubstitutedC₃-C₈ cycloalkylene. In embodiments, L³ is R²⁹-substituted orunsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, L³ isR²⁹-substituted or unsubstituted C₆-C₁₀ arylene. In embodiments, L³ isR²⁹-substituted or unsubstituted 5 to 10 membered heteroarylene. Inembodiments, L³ is R²⁹-substituted C₁-C₂₀ alkylene. In embodiments, L³is R²⁹-substituted 2 to 20 membered heteroalkylene. In embodiments, L³is R²⁹-substituted C₃-C₈ cycloalkylene. In embodiments, L³ isR²⁹-substituted 3 to 8 membered heterocycloalkylene. In embodiments, L³is R²⁹-substituted C₆-C₁₀ arylene. In embodiments, L³ is R²⁹-substituted5 to 10 membered heteroarylene. In embodiments, L³ is unsubstitutedC₁-C₂₀ alkylene. In embodiments, L³ is unsubstituted 2 to 20 memberedheteroalkylene. In embodiments, L³ is unsubstituted C₃-C₈ cycloalkylene.In embodiments, L³ is unsubstituted 3 to 8 membered heterocycloalkylene.In embodiments, L³ is unsubstituted C₆-C₁₀ arylene. In embodiments, L³is unsubstituted 5 to 10 membered heteroarylene. In embodiments, L³ isR²⁹-substituted C₁-C₁₅ alkylene. In embodiments, L³ is R²⁹-substituted 2to 15 membered heteroalkylene. In embodiments, L³ is R²⁹-substitutedC₃-C₆ cycloalkylene. In embodiments, L³ is R²⁹-substituted 3 to 6membered heterocycloalkylene. In embodiments, L³ is R²⁹-substitutedphenylene. In embodiments, L³ is R²⁹-substituted 5 to 6 memberedheteroarylene. In embodiments, L³ is unsubstituted C₁-C₁₅ alkylene. Inembodiments, L³ is unsubstituted 2 to 15 membered heteroalkylene. Inembodiments, L³ is unsubstituted C₃-C₆ cycloalkylene. In embodiments, L³is unsubstituted 3 to 6 membered heterocycloalkylene. In embodiments, L³is unsubstituted phenylene. In embodiments, L³ is unsubstituted 5 to 6membered heteroarylene. In embodiments, L³ is R²⁹-substituted C₁-C₁₀alkylene. In embodiments, L³ is R²⁹-substituted 2 to 10 memberedheteroalkylene. In embodiments, L³ is R²⁹-substituted C₄-C₆cycloalkylene. In embodiments, L³ is R²⁹-substituted 4 to 6 memberedheterocycloalkylene. In embodiments, L³ is R²⁹-substituted phenylene. Inembodiments, L³ is R²⁹-substituted 5 membered heteroarylene. Inembodiments, L³ is R²⁹-substituted C₁-C₈ alkylene. In embodiments, L³ isR²⁹-substituted 2 to 8 membered heteroalkylene. In embodiments, L³ isR²⁹-substituted C₅-C₆ cycloalkylene. In embodiments, L³ isR²⁹-substituted 5 to 6 membered heterocycloalkylene. In embodiments, L³is R²⁹-substituted 6 membered heteroarylene. In embodiments, L³ isR²⁹-substituted C₁-C₆ alkylene. In embodiments, L³ is R²⁹-substituted 2to 6 membered heteroalkylene. In embodiments, L³ is R²⁹-substitutedC₆-C₂₀ alkylene. In embodiments, L³ is R²⁹-substituted 6 to 20 memberedheteroalkylene. In embodiments, L³ is unsubstituted C₁-C₁₀ alkylene. Inembodiments, L³ is unsubstituted 2 to 10 membered heteroalkylene. Inembodiments, L³ is unsubstituted C₄-C₆ cycloalkylene. In embodiments, L³is unsubstituted 4 to 6 membered heterocycloalkylene. In embodiments, L³is unsubstituted phenylene. In embodiments, L³ is unsubstituted 5membered heteroarylene. In embodiments, L³ is unsubstituted C₁-C₈alkylene. In embodiments, L³ is unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L³ is unsubstituted C₅-C₆ cycloalkylene.In embodiments, L³ is unsubstituted 5 to 6 membered heterocycloalkylene.In embodiments, L³ is unsubstituted 6 membered heteroarylene. Inembodiments, L³ is unsubstituted C₁-C₆ alkylene. In embodiments, L³ isunsubstituted 2 to 6 membered heteroalkylene. In embodiments, L³ isunsubstituted C₆-C₂₀ alkylene. In embodiments, L³ is unsubstituted 6 to20 membered heteroalkylene.

R²⁹ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R³⁰-substituted or unsubstituted alkyl, R³⁰-substituted or unsubstitutedheteroalkyl, R³⁰-substituted or unsubstituted cycloalkyl, R³⁰substituted or unsubstituted heterocycloalkyl, R³⁰-substituted orunsubstituted aryl, or R³⁰-substituted or unsubstituted heteroaryl.

In embodiments, R²⁹ is independently —NH₂. In embodiments, R²⁹ isindependently —OH. In embodiments, R²⁹ is independently halogen. Inembodiments, R²⁹ is independently —CN. In embodiments, R²⁹ isindependently oxo. In embodiments, R²⁹ is independently —CF₃. Inembodiments, R²⁹ is independently —COOH. In embodiments, R²⁹ isindependently —CONH₂. In embodiments, R²⁹ is independently —NO₂. Inembodiments, R²⁹ is independently —SH. In embodiments, R²⁹ isindependently —SO₃H. In embodiments, R²⁹ is independently —SO₄H. Inembodiments, R²⁹ is independently —SO₂NH₂. In embodiments, R²⁹ isindependently —NHNH₂. In embodiments, R²⁹ is independently —ONH₂. Inembodiments, R²⁹ is independently —NHC═(O)NHNH₂. In embodiments, R²⁹ isindependently —NHC═(O) NH₂. In embodiments, R²⁹ is independently—NHSO₂H. In embodiments, R²⁹ is independently —NHC═(O)H. In embodiments,R²⁹ is independently —NHC(O)—OH. In embodiments, R²⁹ is independently—NHOH. In embodiments, R²⁹ is independently —OCF₃. In embodiments, R²⁹is independently —OCHF₂. In embodiments, R²⁹ is independently —CCl₃. Inembodiments, R²⁹ is independently —CBr₃. In embodiments, R²⁹ isindependently —Cl₃. In embodiments, R²⁹ is independently —F. Inembodiments, R²⁹ is independently —Cl. In embodiments, R²⁹ isindependently —Br. In embodiments, R²⁹ is independently —I. Inembodiments, R²⁹ is independently R³⁰-substituted C₁-C₄ alkyl. Inembodiments, R²⁹ is independently R³⁰-substituted 2 to 4 memberedheteroalkyl. In embodiments, R²⁹ is independently R³⁰-substituted C₃-C₆cycloalkyl. In embodiments, R²⁹ is independently R³⁰-substituted 3 to 6membered heterocycloalkyl. In embodiments, R²⁹ is independentlyR³⁰-substituted phenyl. In embodiments, R²⁹ is independentlyR³⁰-substituted 5 to 6 membered heteroaryl. In embodiments, R²⁹ isindependently unsubstituted C₁-C₄ alkyl. In embodiments, R²⁹ isindependently unsubstituted 2 to 4 membered heteroalkyl. In embodiments,R²⁹ is independently unsubstituted C₃-C₆ cycloalkyl. In embodiments, R²⁹is independently unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R²⁹ is independently unsubstituted phenyl. In embodiments,R²⁹ is independently unsubstituted 5 to 6 membered heteroaryl.

R³⁰ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R³¹-substituted or unsubstituted alkyl, R³¹-substituted or unsubstitutedheteroalkyl, R³¹-substituted or unsubstituted cycloalkyl,R³¹-substituted or unsubstituted heterocycloalkyl, R³¹-substituted orunsubstituted aryl, or R³¹-substituted or unsubstituted heteroaryl.

In embodiments, R³⁰ is independently —NH₂. In embodiments, R³⁰ isindependently —OH. In embodiments, R³⁰ is independently halogen. Inembodiments, R³⁰ is independently —CN. In embodiments, R³⁰ isindependently oxo. In embodiments, R³⁰ is independently —CF₃. Inembodiments, R³⁰ is independently —COOH. In embodiments, R³⁰ isindependently —CONH₂. In embodiments, R³⁰ is independently —NO₂. Inembodiments, R³⁰ is independently —SH. In embodiments, R³⁰ isindependently —SO₃H. In embodiments, R³⁰ is independently —SO₄H. Inembodiments, R³⁰ is independently —SO₂NH₂. In embodiments, R³⁰ isindependently —NHNH₂. In embodiments, R³⁰ is independently —ONH₂. Inembodiments, R³⁰ is independently —NHC═(O)NHNH₂. In embodiments, R³⁰ isindependently —NHC═(O) NH₂. In embodiments, R³⁰ is independently—NHSO₂H. In embodiments, R³⁰ is independently —NHC═(O)H. In embodiments,R³⁰ is independently —NHC(O)—OH. In embodiments, R³⁰ is independently—NHOH. In embodiments, R³⁰ is independently —OCF₃. In embodiments, R³⁰is independently —OCHF₂. In embodiments, R³⁰ is independently —CCl₃. Inembodiments, R³⁰ is independently —CBr₃. In embodiments, R³⁰ isindependently —Cl₃. In embodiments, R³⁰ is independently —F. Inembodiments, R³⁰ is independently —Cl. In embodiments, R³⁰ isindependently —Br. In embodiments, R³⁰ is independently —I. Inembodiments, R³⁰ is independently R³¹-substituted C₁-C₄ alkyl. Inembodiments, R³⁰ is independently R³¹-substituted 2 to 4 memberedheteroalkyl. In embodiments, R³⁰ is independently R³¹-substituted C₃-C₆cycloalkyl. In embodiments, R³⁰ is independently R³¹-substituted 3 to 6membered heterocycloalkyl. In embodiments, R³⁰ is independentlyR³¹-substituted phenyl. In embodiments, R³⁰ is independentlyR³¹-substituted 5 to 6 membered heteroaryl. In embodiments, R³⁰ isindependently unsubstituted C₁-C₄ alkyl. In embodiments, R³⁰ isindependently unsubstituted 2 to 4 membered heteroalkyl. In embodiments,R³⁰ is independently unsubstituted C₃-C₆ cycloalkyl. In embodiments, R³⁰is independently unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R³⁰ is independently unsubstituted phenyl. In embodiments,R³⁰ is independently unsubstituted 5 to 6 membered heteroaryl.

In some embodiments of the compounds provided herein, L⁴ isindependently a bond, R³²-substituted or unsubstituted alkylene,R³²-substituted or unsubstituted heteroalkylene, R³²-substituted orunsubstituted cycloalkylene, R³²-substituted or unsubstitutedheterocycloalkylene, R³²-substituted or unsubstituted arylene, orR³²-substituted or unsubstituted heteroarylene.

In embodiments, L⁴ is a bond, —NH—, —NR³²—, —S—, —O—, —C(O)—, —NHC(O)—,—C(O)NH—, —NHC(O)NH—, —NHC(NH)NH—, —C(S)—, R³²-substituted orunsubstituted C₁-C₂₀ alkylene, R³²-substituted or unsubstituted 2 to 20membered heteroalkylene, R³²-substituted or unsubstituted C₃-C₈cycloalkylene, R³²-substituted or unsubstituted 3 to 8 memberedheterocycloalkylene, R³²-substituted or unsubstituted C₆-C₁₀ arylene, orR³²-substituted or unsubstituted 5 to 10 membered heteroarylene. Inembodiments, L⁴ is a bond. In embodiments, L⁴ is —NH—. In embodiments,L⁴ is —NR³²—. In embodiments, L⁴ is —S—. In embodiments, L⁴ is —O—. Inembodiments, L⁴ is —C(O)—. In embodiments, L⁴ is —NHC(O)—. Inembodiments, L⁴ is —C(O)NH—. In embodiments, L⁴ is —NHC(O)NH—. Inembodiments, L⁴ is —NHC(NH)NH—. In embodiments, L⁴ is —C(S)—. Inembodiments, L⁴ is R³²-substituted or unsubstituted C₁-C₂₀ alkylene. Inembodiments, L⁴ is R³²-substituted or unsubstituted 2 to 20 memberedheteroalkylene. In embodiments, L⁴ is R³²-substituted or unsubstitutedC₃-C₈ cycloalkylene. In embodiments, L⁴ is R³²-substituted orunsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, L⁴ isR³²-substituted or unsubstituted C₆-C₁₀ arylene. In embodiments, L⁴ isR³²-substituted or unsubstituted 5 to 10 membered heteroarylene. Inembodiments, L⁴ is R³²-substituted C₁-C₂₀ alkylene. In embodiments, L⁴is R³²-substituted 2 to 20 membered heteroalkylene. In embodiments, L⁴is R³²-substituted C₃-C₈ cycloalkylene. In embodiments, L⁴ isR³²-substituted 3 to 8 membered heterocycloalkylene. In embodiments, L⁴is R³²-substituted C₆-C₁₀ arylene. In embodiments, L⁴ is R³²-substituted5 to 10 membered heteroarylene. In embodiments, L⁴ is unsubstitutedC₁-C₂₀ alkylene. In embodiments, L⁴ is unsubstituted 2 to 20 memberedheteroalkylene. In embodiments, L⁴ is unsubstituted C₃-C₈ cycloalkylene.In embodiments, L⁴ is unsubstituted 3 to 8 membered heterocycloalkylene.In embodiments, L⁴ is unsubstituted C₆-C₁₀ arylene. In embodiments, L⁴is unsubstituted 5 to 10 membered heteroarylene. In embodiments, L⁴ isR³²-substituted C₁-C₁₅ alkylene. In embodiments, L⁴ is R³²-substituted 2to 15 membered heteroalkylene. In embodiments, L⁴ is R³²-substitutedC₃-C₆ cycloalkylene. In embodiments, L⁴ is R³²-substituted 3 to 6membered heterocycloalkylene. In embodiments, L⁴ is R³²-substitutedphenylene. In embodiments, L⁴ is R³²-substituted 5 to 6 memberedheteroarylene. In embodiments, L⁴ is unsubstituted C₁-C₁₅ alkylene. Inembodiments, L⁴ is unsubstituted 2 to 15 membered heteroalkylene. Inembodiments, L⁴ is unsubstituted C₃-C₆ cycloalkylene. In embodiments, L⁴is unsubstituted 3 to 6 membered heterocycloalkylene. In embodiments, L⁴is unsubstituted phenylene. In embodiments, L⁴ is unsubstituted 5 to 6membered heteroarylene. In embodiments, L⁴ is R³²-substituted C₁-C₁₀alkylene. In embodiments, L⁴ is R³²-substituted 2 to 10 memberedheteroalkylene. In embodiments, L⁴ is R³²-substituted C₄-C₆cycloalkylene. In embodiments, L⁴ is R³²-substituted 4 to 6 memberedheterocycloalkylene. In embodiments, L⁴ is R³²-substituted phenylene. Inembodiments, L⁴ is R³²-substituted 5 membered heteroarylene. Inembodiments, L⁴ is R³²-substituted C₁-C₈ alkylene. In embodiments, L⁴ isR³²-substituted 2 to 8 membered heteroalkylene. In embodiments, L⁴ isR³²-substituted C₅-C₆ cycloalkylene. In embodiments, L⁴ isR³²-substituted 5 to 6 membered heterocycloalkylene. In embodiments, L⁴is R³²-substituted 6 membered heteroarylene. In embodiments, L⁴ isR³²-substituted C₁-C₆ alkylene. In embodiments, L⁴ is R³²-substituted 2to 6 membered heteroalkylene. In embodiments, L⁴ is R³²-substitutedC₆-C₂₀ alkylene. In embodiments, L⁴ is R³²-substituted 6 to 20 memberedheteroalkylene. In embodiments, L⁴ is unsubstituted C₁-C₁₀ alkylene. Inembodiments, L⁴ is unsubstituted 2 to 10 membered heteroalkylene. Inembodiments, L⁴ is unsubstituted C₄-C₆ cycloalkylene. In embodiments, L⁴is unsubstituted 4 to 6 membered heterocycloalkylene. In embodiments, L⁴is unsubstituted phenylene. In embodiments, L⁴ is unsubstituted 5membered heteroarylene. In embodiments, L⁴ is unsubstituted C₁-C₈alkylene. In embodiments, L⁴ is unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L⁴ is unsubstituted C₅-C₆ cycloalkylene.In embodiments, L⁴ is unsubstituted 5 to 6 membered heterocycloalkylene.In embodiments, L⁴ is unsubstituted 6 membered heteroarylene. Inembodiments, L⁴ is unsubstituted C₁-C₆ alkylene. In embodiments, L⁴ isunsubstituted 2 to 6 membered heteroalkylene. In embodiments, L⁴ isunsubstituted C₆-C₂₀ alkylene. In embodiments, L⁴ is unsubstituted 6 to20 membered heteroalkylene.

R³² is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R³³-substituted or unsubstituted alkyl, R³³-substituted or unsubstitutedheteroalkyl, R³³-substituted or unsubstituted cycloalkyl, R³³substituted or unsubstituted heterocycloalkyl, R³³-substituted orunsubstituted aryl, or R³³-substituted or unsubstituted heteroaryl.

In embodiments, R³² is independently —NH₂. In embodiments, R³² isindependently —OH. In embodiments, R³² is independently halogen. Inembodiments, R³² is independently —CN. In embodiments, R³² isindependently oxo. In embodiments, R³² is independently —CF₃. Inembodiments, R³² is independently —COOH. In embodiments, R³² isindependently —CONH₂. In embodiments, R³² is independently —NO₂. Inembodiments, R³² is independently —SH. In embodiments, R³² isindependently —SO₃H. In embodiments, R³² is independently —SO₄H. Inembodiments, R³² is independently —SO₂NH₂. In embodiments, R³² isindependently —NHNH₂. In embodiments, R³² is independently —ONH₂. Inembodiments, R³² is independently —NHC═(O)NHNH₂. In embodiments, R³² isindependently —NHC═(O) NH₂. In embodiments, R³² is independently—NHSO₂H. In embodiments, R³² is independently —NHC═(O)H. In embodiments,R³² is independently —NHC(O)—OH. In embodiments, R³² is independently—NHOH. In embodiments, R³² is independently —OCF₃. In embodiments, R³²is independently —OCHF₂. In embodiments, R³² is independently —CCl₃. Inembodiments, R³² is independently —CBr₃. In embodiments, R³² isindependently —Cl₃. In embodiments, R³² is independently —F. Inembodiments, R³² is independently —Cl. In embodiments, R³² isindependently —Br. In embodiments, R³² is independently —I. Inembodiments, R³² is independently R³³-substituted C₁-C₄ alkyl. Inembodiments, R³² is independently R³³-substituted 2 to 4 memberedheteroalkyl. In embodiments, R³² is independently R³³-substituted C₃-C₆cycloalkyl. In embodiments, R³² is independently R³³-substituted 3 to 6membered heterocycloalkyl. In embodiments, R³² is independentlyR³³-substituted phenyl. In embodiments, R³² is independentlyR³³-substituted 5 to 6 membered heteroaryl. In embodiments, R³² isindependently unsubstituted C₁-C₄ alkyl. In embodiments, R³² isindependently unsubstituted 2 to 4 membered heteroalkyl. In embodiments,R³² is independently unsubstituted C₃-C₆ cycloalkyl. In embodiments, R³²is independently unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R³² is independently unsubstituted phenyl. In embodiments,R³² is independently unsubstituted 5 to 6 membered heteroaryl.

R³³ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R³⁴-substituted or unsubstituted alkyl, R³⁴-substituted or unsubstitutedheteroalkyl, R³⁴-substituted or unsubstituted cycloalkyl,R³⁴-substituted or unsubstituted heterocycloalkyl, R³⁴-substituted orunsubstituted aryl, or R³⁴-substituted or unsubstituted heteroaryl.

In embodiments, R³³ is independently —NH₂. In embodiments, R³³ isindependently —OH. In embodiments, R³³ is independently halogen. Inembodiments, R³³ is independently —CN. In embodiments, R³³ isindependently oxo. In embodiments, R³³ is independently —CF₃. Inembodiments, R³³ is independently —COOH. In embodiments, R³³ isindependently —CONH₂. In embodiments, R³³ is independently —NO₂. Inembodiments, R³³ is independently —SH. In embodiments, R³³ isindependently —SO₃H. In embodiments, R³³ is independently —SO₄H. Inembodiments, R³³ is independently —SO₂NH₂. In embodiments, R³³ isindependently —NHNH₂. In embodiments, R³³ is independently —ONH₂. Inembodiments, R³³ is independently —NHC═(O)NHNH₂. In embodiments, R³³ isindependently —NHC═(O) NH₂. In embodiments, R³³ is independently—NHSO₂H. In embodiments, R³³ is independently —NHC═(O)H. In embodiments,R³³ is independently —NHC(O)—OH. In embodiments, R³³ is independently—NHOH. In embodiments, R³³ is independently —OCF₃. In embodiments, R³³is independently —OCHF₂. In embodiments, R³³ is independently —CCl₃. Inembodiments, R³³ is independently —CBr₃. In embodiments, R³³ isindependently —Cl₃. In embodiments, R³³ is independently —F. Inembodiments, R³³ is independently —Cl. In embodiments, R³³ isindependently —Br. In embodiments, R³³ is independently —I. Inembodiments, R³³ is independently R³⁴-substituted C₁-C₄ alkyl. Inembodiments, R³³ is independently R³⁴-substituted 2 to 4 memberedheteroalkyl. In embodiments, R³³ is independently R³⁴-substituted C₃-C₆cycloalkyl. In embodiments, R³³ is independently R³⁴-substituted 3 to 6membered heterocycloalkyl. In embodiments, R³³ is independentlyR³⁴-substituted phenyl. In embodiments, R³³ is independentlyR³⁴-substituted 5 to 6 membered heteroaryl. In embodiments, R³³ isindependently unsubstituted C₁-C₄ alkyl. In embodiments, R³³ isindependently unsubstituted 2 to 4 membered heteroalkyl. In embodiments,R³³ is independently unsubstituted C₃-C₆ cycloalkyl. In embodiments, R³³is independently unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R³³ is independently unsubstituted phenyl. In embodiments,R³³ is independently unsubstituted 5 to 6 membered heteroaryl.

In some embodiments of the compounds provided herein, L⁵ isindependently a bond, R³⁵-substituted or unsubstituted alkylene,R³⁵-substituted or unsubstituted heteroalkylene, R³⁵-substituted orunsubstituted cycloalkylene, R³⁵-substituted or unsubstitutedheterocycloalkylene, R³⁵-substituted or unsubstituted arylene, orR³⁵-substituted or unsubstituted heteroarylene.

In embodiments, L⁵ is a bond, —NH—, —NR³⁵—, —S—, —O—, —C(O)—, —NHC(O)—,—C(O)NH—, —NHC(O)NH—, —NHC(NH)NH—, —C(S)—, R³⁵-substituted orunsubstituted C₁-C₂₀ alkylene, R³⁵-substituted or unsubstituted 2 to 20membered heteroalkylene, R³⁵-substituted or unsubstituted C₃-C₈cycloalkylene, R³⁵-substituted or unsubstituted 3 to 8 memberedheterocycloalkylene, R³⁵-substituted or unsubstituted C₆-C₁₀ arylene, orR³⁵-substituted or unsubstituted 5 to 10 membered heteroarylene. Inembodiments, L⁵ is a bond. In embodiments, L⁵ is —NH—. In embodiments,L⁵ is —NR³⁵—. In embodiments, L⁵ is —S—. In embodiments, L⁵ is —O—. Inembodiments, L⁵ is —C(O)—. In embodiments, L⁵ is —NHC(O)—. Inembodiments, L⁵ is —C(O)NH—. In embodiments, L⁵ is —NHC(O)NH—. Inembodiments, L⁵ is —NHC(NH)NH—. In embodiments, L⁵ is —C(S)—. Inembodiments, L⁵ is R³⁵-substituted or unsubstituted C₁-C₂₀ alkylene. Inembodiments, L⁵ is R³⁵-substituted or unsubstituted 2 to 20 memberedheteroalkylene. In embodiments, L⁵ is R³⁵-substituted or unsubstitutedC₃-C₈ cycloalkylene. In embodiments, L⁵ is R³⁵-substituted orunsubstituted 3 to 8 membered heterocycloalkylene. In embodiments, L⁵ isR³⁵-substituted or unsubstituted C₆-C₁₀ arylene. In embodiments, L⁵ isR³⁵-substituted or unsubstituted 5 to 10 membered heteroarylene. Inembodiments, L⁵ is R³⁵-substituted C₁-C₂₀ alkylene. In embodiments, L⁵is R³⁵-substituted 2 to 20 membered heteroalkylene. In embodiments, L⁵is R³⁵-substituted C₃-C₈ cycloalkylene. In embodiments, L⁵ isR³⁵-substituted 3 to 8 membered heterocycloalkylene. In embodiments, L⁵is R³⁵-substituted C₆-C₁₀ arylene. In embodiments, L⁵ is R³⁵-substituted5 to 10 membered heteroarylene. In embodiments, L⁵ is unsubstitutedC₁-C₂₀ alkylene. In embodiments, L⁵ is unsubstituted 2 to 20 memberedheteroalkylene. In embodiments, L⁵ is unsubstituted C₃-C₈ cycloalkylene.In embodiments, L⁵ is unsubstituted 3 to 8 membered heterocycloalkylene.In embodiments, L⁵ is unsubstituted C₆-C₁₀ arylene. In embodiments, L⁵is unsubstituted 5 to 10 membered heteroarylene. In embodiments, L⁵ isR³⁵-substituted C₁-C₁₅ alkylene. In embodiments, L⁵ is R³⁵-substituted 2to 15 membered heteroalkylene. In embodiments, L⁵ is R³⁵-substitutedC₃-C₆ cycloalkylene. In embodiments, L⁵ is R³⁵-substituted 3 to 6membered heterocycloalkylene. In embodiments, L⁵ is R³⁵-substitutedphenylene. In embodiments, L⁵ is R³⁵-substituted 5 to 6 memberedheteroarylene. In embodiments, L⁵ is unsubstituted C₁-C₁₅ alkylene. Inembodiments, L⁵ is unsubstituted 2 to 15 membered heteroalkylene. Inembodiments, L⁵ is unsubstituted C₃-C₆ cycloalkylene. In embodiments, L⁵is unsubstituted 3 to 6 membered heterocycloalkylene. In embodiments, L⁵is unsubstituted phenylene. In embodiments, L⁵ is unsubstituted 5 to 6membered heteroarylene. In embodiments, L⁵ is R³⁵-substituted C₁-C₁₀alkylene. In embodiments, L⁵ is R³⁵-substituted 2 to 10 memberedheteroalkylene. In embodiments, L⁵ is R³⁵-substituted C₄-C₆cycloalkylene. In embodiments, L⁵ is R³⁵-substituted 4 to 6 memberedheterocycloalkylene. In embodiments, L⁵ is R³⁵-substituted phenylene. Inembodiments, L⁵ is R³⁵-substituted 5 membered heteroarylene. Inembodiments, L⁵ is R³⁵-substituted C₁-C₈ alkylene. In embodiments, L⁵ isR³⁵-substituted 2 to 8 membered heteroalkylene. In embodiments, L⁵ isR³⁵-substituted C₅-C₆ cycloalkylene. In embodiments, L⁵ isR³⁵-substituted 5 to 6 membered heterocycloalkylene. In embodiments, L⁵is R³⁵-substituted 6 membered heteroarylene. In embodiments, L⁵ isR³⁵-substituted C₁-C₆ alkylene. In embodiments, L⁵ is R³⁵-substituted 2to 6 membered heteroalkylene. In embodiments, L⁵ is R³⁵-substitutedC₆-C₂₀ alkylene. In embodiments, L⁵ is R³⁵-substituted 6 to 20 memberedheteroalkylene. In embodiments, L⁵ is unsubstituted C₁-C₁₀ alkylene. Inembodiments, L⁵ is unsubstituted 2 to 10 membered heteroalkylene. Inembodiments, L⁵ is unsubstituted C₄-C₆ cycloalkylene. In embodiments, L⁵is unsubstituted 4 to 6 membered heterocycloalkylene. In embodiments, L⁵is unsubstituted phenylene. In embodiments, L⁵ is unsubstituted 5membered heteroarylene. In embodiments, L⁵ is unsubstituted C₁-C₈alkylene. In embodiments, L⁵ is unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L⁵ is unsubstituted C₅-C₆ cycloalkylene.In embodiments, L¹ is unsubstituted 5 to 6 membered heterocycloalkylene.In embodiments, L⁵ is unsubstituted 6 membered heteroarylene. Inembodiments, L⁵ is unsubstituted C₁-C₆ alkylene. In embodiments, L⁵ isunsubstituted 2 to 6 membered heteroalkylene. In embodiments, L⁵ isunsubstituted C₆-C₂₀ alkylene. In embodiments, L⁵ is unsubstituted 6 to20 membered heteroalkylene.

R³⁵ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R³⁶-substituted or unsubstituted alkyl, R³⁶-substituted or unsubstitutedheteroalkyl, R³⁶-substituted or unsubstituted cycloalkyl, R³⁶substituted or unsubstituted heterocycloalkyl, R³⁶-substituted orunsubstituted aryl, or R³⁶-substituted or unsubstituted heteroaryl.

In embodiments, R³⁵ is independently —NH₂. In embodiments, R³⁵ isindependently —OH. In embodiments, R³⁵ is independently halogen. Inembodiments, R³⁵ is independently —CN. In embodiments, R³⁵ isindependently oxo. In embodiments, R³⁵ is independently —CF₃. Inembodiments, R³⁵ is independently —COOH. In embodiments, R³⁵ isindependently —CONH₂. In embodiments, R³⁵ is independently —NO₂. Inembodiments, R³⁵ is independently —SH. In embodiments, R³⁵ isindependently —SO₃H. In embodiments, R³⁵ is independently —SO₄H. Inembodiments, R³⁵ is independently —SO₂NH₂. In embodiments, R³⁵ isindependently —NHNH₂. In embodiments, R³⁵ is independently —ONH₂. Inembodiments, R³⁵ is independently —NHC═(O)NHNH₂. In embodiments, R³⁵ isindependently —NHC═(O) NH₂. In embodiments, R³⁵ is independently—NHSO₂H. In embodiments, R³⁵ is independently —NHC═(O)H. In embodiments,R³⁵ is independently —NHC(O)—OH. In embodiments, R³⁵ is independently—NHOH. In embodiments, R³⁵ is independently —OCF₃. In embodiments, R³⁵is independently —OCHF₂. In embodiments, R³⁵ is independently —CCl₃. Inembodiments, R³⁵ is independently —CBr₃. In embodiments, R³⁵ isindependently —Cl₃. In embodiments, R³⁵ is independently —F. Inembodiments, R³⁵ is independently —Cl. In embodiments, R³⁵ isindependently —Br. In embodiments, R³⁵ is independently —I. Inembodiments, R³⁵ is independently R³⁶-substituted C₁-C₄ alkyl. Inembodiments, R³⁵ is independently R³⁶-substituted 2 to 4 memberedheteroalkyl. In embodiments, R³⁵ is independently R³⁶-substituted C₃-C₆cycloalkyl. In embodiments, R³⁵ is independently R³⁶-substituted 3 to 6membered heterocycloalkyl. In embodiments, R³⁵ is independentlyR³⁶-substituted phenyl. In embodiments, R³⁵ is independentlyR³⁶-substituted 5 to 6 membered heteroaryl. In embodiments, R³⁵ isindependently unsubstituted C₁-C₄ alkyl. In embodiments, R³⁵ isindependently unsubstituted 2 to 4 membered heteroalkyl. In embodiments,R³⁵ is independently unsubstituted C₃-C₆ cycloalkyl. In embodiments, R³⁵is independently unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R³⁵ is independently unsubstituted phenyl. In embodiments,R³⁵ is independently unsubstituted 5 to 6 membered heteroaryl.

R³⁶ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R³⁷-substituted or unsubstituted alkyl, R³⁷-substituted or unsubstitutedheteroalkyl, R³⁷-substituted or unsubstituted cycloalkyl,R³⁷-substituted or unsubstituted heterocycloalkyl, R³⁷-substituted orunsubstituted aryl, or R³⁷-substituted or unsubstituted heteroaryl.

In embodiments, R³⁶ is independently —NH₂. In embodiments, R³⁶ isindependently —OH. In embodiments, R³⁶ is independently halogen. Inembodiments, R³⁶ is independently —CN. In embodiments, R³⁶ isindependently oxo. In embodiments, R³⁶ is independently —CF₃. Inembodiments, R³⁶ is independently —COOH. In embodiments, R³⁶ isindependently —CONH₂. In embodiments, R³⁶ is independently —NO₂. Inembodiments, R³⁶ is independently —SH. In embodiments, R³⁶ isindependently —SO₃H. In embodiments, R³⁶ is independently —SO₄H. Inembodiments, R³⁶ is independently —SO₂NH₂. In embodiments, R³⁶ isindependently —NHNH₂. In embodiments, R³⁶ is independently —ONH₂. Inembodiments, R³⁶ is independently —NHC═(O)NHNH₂. In embodiments, R³⁶ isindependently —NHC═(O) NH₂. In embodiments, R³⁶ is independently—NHSO₂H. In embodiments, R³⁶ is independently —NHC═(O)H. In embodiments,R³⁶ is independently —NHC(O)—OH. In embodiments, R³⁶ is independently—NHOH. In embodiments, R³⁶ is independently —OCF₃. In embodiments, R³⁶is independently —OCHF₂. In embodiments, R³⁶ is independently —CCl₃. Inembodiments, R³⁶ is independently —CBr₃. In embodiments, R³⁶ isindependently —Cl₃. In embodiments, R³⁶ is independently —F. Inembodiments, R³⁶ is independently —Cl. In embodiments, R³⁶ isindependently —Br. In embodiments, R³⁶ is independently —I. Inembodiments, R³⁶ is independently R³⁷-substituted C₁-C₄ alkyl. Inembodiments, R³⁶ is independently R³⁷-substituted 2 to 4 memberedheteroalkyl. In embodiments, R³⁶ is independently R³⁷-substituted C₃-C₆cycloalkyl. In embodiments, R³⁶ is independently R³⁷-substituted 3 to 6membered heterocycloalkyl. In embodiments, R³⁶ is independentlyR³⁷-substituted phenyl. In embodiments, R³⁶ is independentlyR³⁷-substituted 5 to 6 membered heteroaryl. In embodiments, R³⁶ isindependently unsubstituted C₁-C₄ alkyl. In embodiments, R³⁶ isindependently unsubstituted 2 to 4 membered heteroalkyl. In embodiments,R³⁶ is independently unsubstituted C₃-C₆ cycloalkyl. In embodiments, R³⁶is independently unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R³⁶ is independently unsubstituted phenyl. In embodiments,R³⁶ is independently unsubstituted 5 to 6 membered heteroaryl.

In some embodiments, R³ is substituted heteroaryl; L¹ is L²-L³-L⁴-L⁵; L²is —CH₂CH₂OCH₂—; L³ is 5 to 10 membered heteroarylene; L⁴ is—(CH₂CH₂O)_(b)—; b is an integer from 2 to 8; L⁵ is—CH₂CH₂C═(O)NH(CH₂)_(b10)—; and b10 is an integer from 1 to 6. In someembodiments, R³ is substituted bicyclic heteroaryl; L¹ is L²-L³-L⁴-L⁵;L² is —CH₂CH₂OCH₂—; L³ is 5 to 10 membered heteroarylene; L⁴ is—(CH₂CH₂O)_(b)—; b is an integer from 2 to 8; L⁵ is—CH₂CH₂C═(O)NH(CH₂)_(b10)—; and b10 is an integer from 1 to 6. In someembodiments, R³ is heteroaryl substituted with —NH₂ or —OH; L¹ isL²-L³-L⁴-L⁵; L² is —CH₂CH₂OCH₂—; L³ is 5 to 10 membered heteroarylene;L⁴ is —(CH₂CH₂O)_(b)—; b is an integer from 2 to 8; L⁵ is—CH₂CH₂C═(O)NH(CH₂)_(b10)—; and b10 is an integer from 1 to 6. In someembodiments, R³ is benzoxazolyl substituted with —NH₂ or —OH; L¹ isL²-L³-L⁴-L⁵; L² is —CH₂CH₂OCH₂—; L³ is 5 to 10 membered heteroarylene;L⁴ is —(CH₂CH₂O)_(b)—; b is an integer from 2 to 8; L⁵ is—CH₂CH₂C═(O)NH(CH₂)_(b10)—; and b10 is an integer from 1 to 6. In someembodiments, R³ is benzoxazolyl substituted with —NH₂ or —OH; L¹ isL²-L³-L⁴-L⁵; L² is —CH₂CH₂OCH₂—; L³ is triazolylene; L⁴ is—(CH₂CH₂O)_(b)—; b is an integer from 4 to 8; and L⁵ is—CH₂CH₂C═(O)NH(CH₂)₄.

R²², R²⁵, R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵, and R⁵⁸, areindependently hydrogen, oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, orunsubstituted heteroaryl.

In embodiments, R²², R²⁵, R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹, R⁵²,R⁵⁵, and/or R⁵⁸, are independently —NH₂. In embodiments, R²², R²⁵, R²⁸,R³, R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵, and/or R⁵⁸, are independently—OH. In embodiments, R²², R²⁵, R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹,R⁵², R⁵⁵, and/or R⁵⁸, are independently halogen. In embodiments, R²²,R²⁵, R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵, and/or R⁵⁸, areindependently —CN. In embodiments, R²², R²⁵, R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰,R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵, and/or R⁵⁸, are independently oxo. Inembodiments, R²², R²⁵, R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵,and/or R⁵⁸, are independently —CF₃. In embodiments, R²², R²⁵, R²⁸, R³¹,R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵, and/or R⁵⁸, are independently—COOH. In embodiments, R²², R, R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹,R⁵², R⁵⁵, and/or R⁵⁸, are independently —CONH₂. In embodiments, R²²,R²⁵, R²⁸, R³, R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵, and/or R⁵⁸, areindependently —NO₂. In embodiments, R²², R²⁵, R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰,R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵, and/or R⁵⁸, are independently —SH. Inembodiments, R²², R²⁵, R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵,and/or R⁵⁸, are independently —SO₃H. In embodiments, R²², R²⁵, R²⁸, R³¹,R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵, and/or R⁵⁸, are independently—SO₄H. In embodiments, R²², R²⁵, R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹,R⁵², R⁵⁵, and/or R⁵⁸, are independently —SO₂NH₂. In embodiments, R²²,R²⁵, R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵, and/or R⁵⁸, areindependently —NHNH₂. In embodiments, R²², R²⁵, R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰,R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵, and/or R⁵⁸, are independently —ONH₂. Inembodiments, R²², R²⁵, R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵,and/or R⁵⁸, are independently —NHC═(O)NHNH₂. In embodiments, R²², R²⁵,R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵, and/or R⁵⁸, areindependently —NHC═(O) NH₂. In embodiments, R²², R²⁵, R²⁸, R³¹, R³⁴,R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵, and/or R⁵⁸, are independently—NHSO₂H. In embodiments, R²², R²⁵, R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶,R⁴⁹, R⁵², R⁵⁵, and/or R⁵⁸, are independently —NHC═(O)H. In embodiments,R²², R²⁵, R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵, and/or R⁵⁸,are independently —NHC(O)—OH. In embodiments, R²², R²⁵, R²⁸, R³¹, R³⁴,R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵, and/or R⁵⁸, are independently —NHOH.In embodiments, R²², R²⁵, R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹, R⁵²,R⁵⁵, and/or R⁵⁸, are independently —OCF₃. In embodiments, R²², R²⁵, R²⁸,R³¹, R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵, and/or R⁵⁸, areindependently —OCHF₂. In embodiments, R²², R²⁵, R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰,R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵, and/or R⁵⁸, are independently —CCl₃. Inembodiments, R²², R²⁵, R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵,and/or R⁵⁸, are independently —CBr₃. In embodiments, R²², R²⁵, R²⁸, R³¹,R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵, and/or R⁵⁸, are independently—Cl₃. In embodiments, R²², R²⁵, R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹,R⁵², R⁵⁵, and/or R⁵⁸, are independently —F. In embodiments, R²², R²⁵,R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵, and/or R⁵⁸, areindependently —Cl. In embodiments, R²², R²⁵, R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰,R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵, and/or R⁵⁸, are independently —Br. Inembodiments, R²², R²⁵, R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵,and/or R⁵⁸, are independently —I. In embodiments, R²², R²⁵, R²⁸, R³¹,R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵, and/or R⁵⁸, are independentlyunsubstituted C₁-C₄ alkyl. In embodiments, R²², R²⁵, R²⁸, R³¹, R³⁴, R³⁷,R⁴⁰, R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵, and/or R⁵⁸, are independentlyunsubstituted 2 to 4 membered heteroalkyl. In embodiments, R²², R²⁵,R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵, and/or R⁵⁸, areindependently unsubstituted C₃-C₆ cycloalkyl. In embodiments, R²², R²⁵,R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵, and/or R⁵⁸, areindependently unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R²², R²⁵, R²⁸, R³¹, R³⁴, R³⁷, R⁴⁴, R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵,and/or R⁵⁸, are independently unsubstituted phenyl. In embodiments, R²²,R²⁵, R²⁸, R³¹, R³⁴, R³⁷, R⁴⁰, R⁴³, R⁴⁶, R⁴⁹, R⁵², R⁵⁵, and/or R⁵⁸, areindependently unsubstituted 5 to 6 membered heteroaryl.

In some embodiments, a compound as described herein may include multipleinstances of R³, R⁷, R⁸, R⁹, R¹⁰, X, m, n, v, and/or other variables. Insuch embodiments, each variable may optional be different and beappropriately labeled to distinguish each group for greater clarity. Forexample, where each R³, R⁷, R⁸, R⁹, R¹⁰, X, m, n, and/or v, isdifferent, they may be referred to, for example, as R^(3.1), R^(3.2),R^(3.3), R^(3.4), R^(3.5), R^(3.6), R^(3.7), R^(7.1), R^(7.2), R^(7.3),R^(7.4), R^(7.5), R^(7.6), R^(7.7), R^(8.1), R^(8.2), R^(8.3), R^(8.4),R^(8.5), R^(8.6), R^(8.7), R^(9.1), R^(9.2), R^(9.3), R^(9.4), R^(9.5),R^(9.6), R^(9.7), R^(10.1), R^(10.2), R^(10.3), R^(10.4), R^(10.5),R^(10.6), R^(10.7), ^(0.1), X^(0.2), X^(0.3), X^(0.4), X^(0.5), X^(0.6),X^(0.7), m^(0.1), m^(0.2), m^(0.3), m^(0.4), m^(0.5), m^(0.6), m^(0.7),n^(0.1), n^(0.2), n^(0.3), n^(0.4), n^(0.5), n^(0.6), n^(0.7), v^(0.1),v^(0.2), v^(0.3), v^(0.4), v^(0.5), v^(0.6), v^(0.7), respectively,wherein the definition of R³ is assumed by R^(3.1), R^(3.2), R^(3.3),R^(3.4), R^(3.5), R^(3.6), R^(3.7), the definition of R⁷ is assumed byR^(7.1), R^(7.2), R^(7.3), R^(7.4), R^(7.5), R^(7.6), R^(7.7), thedefinition of R⁸ is assumed by R^(8.1), R^(8.2), R^(8.3), R^(8.4),R^(8.5), R^(8.6), R^(8.7), the definition of R⁹ is assumed by R^(9.1),R^(9.2), R^(9.3), R^(9.4), R^(9.5), R^(9.6), R^(9.7), the definition ofR¹⁰ is assumed by R^(10.1), R^(10.2), R^(10.3), R^(10.4), R^(10.5),R^(10.6), R^(10.7), the definition of X is assumed by X^(0.1), X^(0.2),X^(0.3), X^(0.4), X^(0.5), X^(0.6), X^(0.7), the definition of m isassumed by m^(0.1), m^(0.2), m^(0.3), m^(0.4), m^(0.5), m^(0.6),m^(0.7), the definition of n is assumed by n^(0.1), n^(0.2), n^(0.3),n^(0.4), n^(0.5), n^(0.6), n^(0.7), the definition of v is assumed byv^(0.1), v^(0.2), v^(0.3), v^(0.4), v^(0.5,) v^(0.6), v^(0.7).

The variables used within a definition of R³, R⁷, R⁸, R⁹, R¹⁰, X, m, n,v, and/or other variables that appear at multiple instances and aredifferent may similarly be appropriately labeled to distinguish eachgroup for greater clarity.

In embodiments, the compound competes with rapamycin for binding tomTORC1. In embodiments, the compound binds an overlapping region ofmTORC1 with the binding region of rapamycin. In embodiments, thecompound competes with ATP for binding to mTOR. In embodiments, thecompound competes with ATP for binding to mTORC1. In embodiments, thecompound competes with rapamycin and ATP for binding to mTORC1.

In embodiments, the compound is an mTORC1 specific inhibitor. Inembodiments, the compound has a slow off-rate from mTORC1. Inembodiments, the compound has an off-rate of slower than 0.1 per minute.In embodiments, the compound has an off-rate of slower than 0.01 perminute. In embodiments, the compound has an off-rate of slower than0.001 per minute. In embodiments, the compound has an off-rate of slowerthan 0.0001 per minute. In embodiments, the compound-mTORC1 complex hasa half-life of at least 10 minutes. In embodiments, the compound-mTORC1complex has a half-life of at least 100 minutes. In embodiments, thecompound-mTORC1 complex has a half-life of at least 300 minutes. Inembodiments, the compound-mTORC1 complex has a half-life of at least1000 minutes. In embodiments, the compound-mTORC1 complex has ahalf-life of at least 3000 minutes. In embodiments, the compound-mTORC1complex has a half-life of at least 10000 minutes.

In embodiments, the compound is

In embodiments, the compound is

In embodiments, the compound is

In embodiments, the compound is

In embodiments, the compound is M-1071. In embodiments, the compound isM-1111. In embodiments, the compound is M-3059. In embodiments, thecompound is M-1115. In embodiments, the compound is not M-1115. Inembodiments, the compound is E1010. In embodiments, the compound isE1035.

In embodiments, the active site mTOR inhibitor is a monovalent MLN0128.

In embodiments, the active site mTOR inhibitor is

wherein R²⁰ is as described herein, including in embodiments. Inembodiments, z20 is an integer from 0 to 4. In embodiments, z20 is 0. Inembodiments, z20 is 1. In embodiments, z20 is 2. In embodiments, z20 is3. In embodiments, z20 is 4. In embodiments, R²⁰ is independently —NH₂.In embodiments, R²⁰ is independently —OH. In embodiments, R²⁰ isindependently halogen. In embodiments, R²⁰ is independently —CN. Inembodiments, R²⁰ is independently oxo. In embodiments, R²⁰ isindependently —CF₃. In embodiments, R²⁰ is independently —COOH. Inembodiments, R²⁰ is independently —CONH₂. In embodiments, R²⁰ isindependently —NO₂. In embodiments, R²⁰ is independently —SH. Inembodiments, R²⁰ is independently —SO₃H. In embodiments, R²⁰ isindependently —SO₄H. In embodiments, R²⁰ is independently —SO₂NH₂. Inembodiments, R²⁰ is independently —NHNH₂. In embodiments, R²⁰ isindependently —ONH₂. In embodiments, R²⁰ is independently —NHC═(O)NHNH₂.In embodiments, R²⁰ is independently —NHC═(O) NH₂. In embodiments, R²⁰is independently —NHSO₂H. In embodiments, R²⁰ is independently—NHC═(O)H. In embodiments, R²⁰ is independently —NHC(O)—OH. Inembodiments, R²⁰ is independently —NHOH. In embodiments, R²⁰ isindependently —OCF₃. In embodiments, R²⁰ is independently —OCHF₂. Inembodiments, R²⁰ is independently a halogen, —CF₃, —CHF₂, —CH₂F, —CN,—NHNH₂, —NO₂, —NH₂, —C(O)H, —C(O)OH, —C(O)NH₂, —OH, —NHC(O)OH, —OCF₃,—OCHF₂, R²¹-substituted or unsubstituted C₁-C₈ alkyl, R²¹-substituted orunsubstituted 2 to 8 membered heteroalkyl, R²¹-substituted orunsubstituted C₃-C₈ cycloalkyl, R²¹-substituted or unsubstituted 3 to 8membered heterocycloalkyl, R²¹-substituted or unsubstituted C₆-C₁₀ aryl,or R²¹-substituted or unsubstituted 5 to 10 membered heteroaryl. Inembodiments, R²⁰ is independently a halogen, —CF₃, —CN, —NH₂, —OH,R²¹-substituted or unsubstituted C₁-C₄ alkyl, R²¹-substituted orunsubstituted 2 to 4 membered heteroalkyl, R²¹-substituted orunsubstituted C₃-C₆ cycloalkyl, R²¹-substituted or unsubstituted 3 to 6membered heterocycloalkyl, R²¹-substituted or unsubstituted phenyl, orR²¹-substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R²⁰ is independently a halogen, —CF₃, —CN, —NH₂, —OH,unsubstituted C₁-C₄ alkyl, or unsubstituted 2 to 4 membered heteroalkyl.In embodiments, R²⁰ is independently a halogen, —CF₃, unsubstitutedmethyl, unsubstituted ethyl, unsubstituted isopropyl, unsubstitutedmethoxy, or unsubstituted ethoxy. In embodiments, R²⁰ is independentlyunsubstituted methyl. In embodiments, R²⁰ is independently unsubstitutedethyl. In embodiments, R²⁰ is independently unsubstituted methoxy. Inembodiments, R²⁰ is independently unsubstituted ethoxy. In embodiments,R²⁰ is independently —CCl₃. In embodiments, R²⁰ is independently —CBr₃.In embodiments, R²⁰ is independently —Cl₃. In embodiments, R²⁰ isindependently —F. In embodiments, R²⁰ is independently —Cl. Inembodiments, R²⁰ is independently —Br. In embodiments, R²⁰ isindependently —I. In embodiments, the active site mTOR inhibitor is

wherein R²⁰ is as described herein, including in embodiments. Inembodiments, the active site mTOR inhibitor is

In embodiments, the active site mTOR inhibitor is

In embodiments, the active site mTOR inhibitor is

In embodiments, the active site mTOR inhibitor is

In embodiments, the active site mTOR inhibitor is

In embodiments, the active site mTOR inhibitor is

In embodiments, the active site mTOR inhibitor is

wherein R²⁰ is as described herein, including in embodiments. z20 is aninteger from 0 to 5. In embodiments, z20 is 0. In embodiments, z20 is 1.In embodiments, z20 is 2. In embodiments, z20 is 3. In embodiments, z20is 4. In embodiments, z20 is 5. In embodiments, R²⁰ is independently—NH₂. In embodiments, R²⁰ is independently —OH. In embodiments, R²⁰ isindependently halogen. In embodiments, R²⁰ is independently —CN. Inembodiments, R²⁰ is independently oxo. In embodiments, R²⁰ isindependently —CF₃. In embodiments, R²⁰ is independently —COOH. Inembodiments, R²⁰ is independently —CONH₂. In embodiments, R²⁰ isindependently —NO₂. In embodiments, R²⁰ is independently —SH. Inembodiments, R²⁰ is independently —SO₃H. In embodiments, R²⁰ isindependently —SO₄H. In embodiments, R²⁰ is independently —SO₂NH₂. Inembodiments, R²⁰ is independently —NHNH₂. In embodiments, R²⁰ isindependently —ONH₂. In embodiments, R²⁰ is independently —NHC═(O)NHNH₂.In embodiments, R²⁰ is independently —NHC═(O) NH₂. In embodiments, R²⁰is independently —NHSO₂H. In embodiments, R²⁰ is independently—NHC═(O)H. In embodiments, R²⁰ is independently —NHC(O)—OH. Inembodiments, R²⁰ is independently —NHOH. In embodiments, R²⁰ isindependently —OCF₃. In embodiments, R²⁰ is independently —OCHF₂. Inembodiments, R²⁰ is independently a halogen, —CF₃, —CHF₂, —CH₂F, —CN,—NHNH₂, —NO₂, —NH₂, —C(O)H, —C(O)OH, —C(O)NH₂, —OH, —NHC(O)OH, —OCF₃,—OCHF₂, R²¹-substituted or unsubstituted C₁-C₈ alkyl, R²¹-substituted orunsubstituted 2 to 8 membered heteroalkyl, R²¹-substituted orunsubstituted C₃-C₈ cycloalkyl, R²¹-substituted or unsubstituted 3 to 8membered heterocycloalkyl, R²¹-substituted or unsubstituted C₆-C₁₀ aryl,or R²¹-substituted or unsubstituted 5 to 10 membered heteroaryl. Inembodiments, R²⁰ is independently a halogen, —CF₃, —CN, —NH₂, —OH,R²¹-substituted or unsubstituted C₁-C₄ alkyl, R²¹-substituted orunsubstituted 2 to 4 membered heteroalkyl, R²¹-substituted orunsubstituted C₃-C₆ cycloalkyl, R²¹-substituted or unsubstituted 3 to 6membered heterocycloalkyl, R²¹-substituted or unsubstituted phenyl, orR²¹-substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R²⁰ is independently a halogen, —CF₃, —CN, —NH₂, —OH,unsubstituted C₁-C₄ alkyl, or unsubstituted 2 to 4 membered heteroalkyl.In embodiments, R²⁰ is independently a halogen, —CF₃, unsubstitutedmethyl, unsubstituted ethyl, unsubstituted isopropyl, unsubstitutedmethoxy, or unsubstituted ethoxy. In embodiments, R²⁰ is independentlyunsubstituted methyl. In embodiments, R²⁰ is independently unsubstitutedethyl. In embodiments, R²⁰ is independently unsubstituted methoxy. Inembodiments, R²⁰ is independently unsubstituted ethoxy. In embodiments,R²⁰ is independently —CCl₃. In embodiments, R²⁰ is independently —CBr₃.In embodiments, R²⁰ is independently —Cl₃. In embodiments, R²⁰ isindependently —F. In embodiments, R²⁰ is independently —Cl. Inembodiments, R²⁰ is independently —Br. In embodiments, R²⁰ isindependently —I. In embodiments, the active site mTOR inhibitor is

wherein R²⁰ is as described herein. In embodiments, the active site mTORinhibitor is

In embodiments, the active site mTOR inhibitor is

In embodiments, the active site mTOR inhibitor is

In embodiments, the active site mTOR inhibitor is

In embodiments, the active site mTOR inhibitor (e.g., asTORi) has aweaker binding affinity for mTOR than MLN0128. In embodiments, theactive site mTOR inhibitor has a binding affinity that results inpreferential binding to mTORC1 over mTORC2 that is greater than the samecompound wherein the active site mTOR inhibitor is MLN0128. Inembodiments, the active site mTOR inhibitor has a binding affinity thatresults in preferential binding to mTORC1 over mTORC2 that is greaterthan the same compound wherein the active site mTOR inhibitor is PP242.In embodiments, the active site mTOR inhibitor has a binding affinitythat results in preferential binding to mTORC1 over mTORC2 that isgreater than the same compound wherein the active site mTOR inhibitor isPP242 wherein the —OH substituent on the indoyly moiety is replaced withan unsubstituted methoxy moiety. Without being limited by mechanism, thecompound may include an active site mTOR inhibitor that results in apreferential binding of the compound to mTORC1 over mTORC2 of at least1.1-fold (e.g., at least 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2,3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300,400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000,8000, 9000,410000, 10000, 20000, 30000, 40000, 50000, 60000, 70000,80000, 90000, 100000, 100000, 200000, 300000, 400000, 500000, 600000,700000, 800000, 900000, or 1000000 fold). Without being limited bymechanism, the compound may include an active site mTOR inhibitor thatresults in a preferential inhibition of mTORC1 over mTORC2 by thecompound of at least 1.1-fold (e.g., at least 1.1, 1.2, 1.3, 1.4, 1.5,1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70,80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000,4000, 5000, 6000, 7000, 8000, 9000, 10000, 10000, 20000, 30000, 40000,50000, 60000, 70000, 80000, 90000, 100000, 100000, 200000, 300000,400000, 500000, 600000, 700000, 800000, 900000, or 1000000 fold).

In embodiments, the compound is included in a drug-eluting stent.

In embodiments, the compound is a compound described herein.

In an aspect is provided a drug-eluting stent comprising a compound asdescribed herein.

B. Pharmaceutical Compositions

In another aspect is provided a pharmaceutical composition including apharmaceutically acceptable excipient and a compound, orpharmaceutically acceptable salt thereof, as described herein, includingembodiments (e.g. in an aspect, embodiment, example, figure, table, orclaim).

In embodiments of the pharmaceutical compositions, the compound, orpharmaceutically acceptable salt thereof, is included in atherapeutically effective amount. In embodiments of the pharmaceuticalcompositions, the compound is included in a drug-eluting stent.

In embodiments of the pharmaceutical compositions, the pharmaceuticalcomposition includes a second agent (e.g. therapeutic agent). Inembodiments of the pharmaceutical compositions, the pharmaceuticalcomposition includes a second agent (e.g. therapeutic agent) in atherapeutically effective amount. In embodiments, the second agent is ananti-cancer agent. In embodiments, the second agent is ananti-autoimmune disease agent. In embodiments, the second agent is ananti-inflammatory disease agent. In embodiments, the second agent is ananti-neurodegenerative disease agent. In embodiments, the second agentis an anti-metabolic disease agent. In embodiments, the second agent isan anti-cardiovascular disease agent. In embodiments, the second agentis an anti-aging agent. In embodiments, the second agent is a longevityagent. In embodiments, the second agent is an agent for treating orpreventing transplant rejection. In embodiments, the second agent is anagent for treating or preventing fungal infection. In embodiments, thesecond agent is immune system repressor. In embodiments, the secondagent is an mTOR modulator. In embodiments, the second agent is an mTORinhibitor. In embodiments, the second agent is an active site mTORinhibitor. In embodiments, the second agent is a rapamycin. Inembodiments, the second agent is a rapamycin analog. In embodiments, thesecond agent is an mTORC1 pathway inhibitor.

C. Methods of Treatment

In an aspect is provided a method of treating a disease associated withan aberrant level of mTORC1 activity in a subject in need of suchtreatment. The disease may be caused by an aberrantly high mTORC1activity (e.g., hyperactivity of mTORC1 or increased level of activityof mTORC1 or increased amount of mTORC1 or mTOR mutations). The methodincludes administering to the subject a compound described herein. Themethod may include administering to the subject a therapeuticallyeffective amount of a compound described herein (e.g., an mTORC1modulator (e.g., inhibitor) as described above).

In an aspect is provided a compound as described herein for use as amedicament. In embodiments, the medicament is useful for treating adisease caused by an aberrantly high mTORC1 activity (e.g.,hyperactivity of mTORC1 or increased level of activity of mTORC1 orincreased amount of mTORC1). The use includes administering to thesubject a compound described herein. The use may include administeringto the subject a therapeutically effective amount of a compounddescribed herein (e.g., an mTORC1 modulator (e.g., inhibitor) asdescribed above).

In an aspect is provided a compound as described herein for use in thetreatment of a disease caused by aberrant levels of mTORC1 activity in asubject in need of such treatment. The disease may be caused by anaberrantly high mTORC1 activity (e.g., hyperactivity of mTORC1 orincreased level of activity of mTORC1 or increased amount of mTORC1).The use includes administering to the subject a compound describedherein. The use may include administering to the subject atherapeutically effective amount of a compound described herein (e.g.,an mTORC1 modulator (e.g., inhibitor) as described above).

mTORC1 hyperactivity is an increased amount of mTORC1 activity comparedto normal levels of mTORC1 activity in a particular subject or apopulation of healthy subjects. The increased amount of mTORC1 activitymay result in, for example, excessive amounts of cell proliferationthereby causing the disease state.

The subject of treatment for the disease is typically a mammal. Themammal treated with the compound (e.g., compound described herein,mTORC1 modulator (e.g., inhibitor)) may be a human, nonhuman primate,and/or non-human mammal (e.g., rodent, canine).

In another aspect is provided a method of treating an mTORC1activity-associated disease in a subject in need of such treatment, themethod including administering a compound, or a pharmaceuticallyacceptable salt thereof, as described herein, including embodiments(e.g. a claim, embodiment, example, table, figure, or claim) to thesubject.

In another aspect is provided a compound as described herein for use asa medicament. In embodiments, the medicament may be useful for treatingan mTORC1 activity-associated disease in a subject in need of suchtreatment. In embodiments, the use may include administering a compound,or a pharmaceutically acceptable salt thereof, as described herein,including embodiments (e.g. an aspect, embodiment, example, table,figure, or claim) to the subject.

In another aspect is provided a compound for use in the treatment of anmTORC1 activity-associated disease in a subject in need of suchtreatment. In embodiments, the use may include administering a compound,or a pharmaceutically acceptable salt thereof, as described herein,including embodiments (e.g. an aspect, embodiment, example, table,figure, or claim) to the subject.

In embodiments, the mTORC1 activity-associated disease or diseaseassociated with aberrant levels of mTORC1 activity is cancer. Inembodiments, the mTORC1 activity-associated disease or diseaseassociated with aberrant levels of mTORC1 activity is an autoimmunedisease. In embodiments, the mTORC1 activity-associated disease ordisease associated with aberrant levels of mTORC1 activity is aninflammatory disease. In embodiments, the mTORC1 activity-associateddisease or disease associated with aberrant levels of mTORC1 activity isa neurodegenerative disease. In embodiments, the mTORC1activity-associated disease or disease associated with aberrant levelsof mTORC1 activity is a metabolic disease. In embodiments, the mTORC1activity-associated disease or disease associated with aberrant levelsof mTORC1 activity is transplant rejection. In embodiments, the mTORC1activity-associated disease or disease associated with aberrant levelsof mTORC1 activity is fungal infection. In embodiments, the mTORC1activity-associated disease or disease associated with aberrant levelsof mTORC1 activity is an inflammatory disease. In embodiments, themTORC1 activity-associated disease or disease associated with aberrantlevels of mTORC1 activity is a cardiovascular disease. In embodiments,the mTORC1 activity-associated disease or disease associated withaberrant levels of mTORC1 activity is aging. In embodiments, the mTORC1activity-associated disease or disease associated with aberrant levelsof mTORC1 activity is dying of an age-related disease. In embodiments,the mTORC1 activity-associated disease or disease associated withaberrant levels of mTORC1 activity is Cancer (e.g., carcinomas,sarcomas, adenocarcinomas, lymphomas, leukemias, solid cancers, lymphoidcancers; cancer of the kidney, breast, lung, bladder, colon, ovarian,prostate, pancreas, stomach, brain, head and neck, skin, uterine,esophagus, liver; testicular cancer, glioma, hepatocarcinoma, lymphoma,including B-acute lymphoblastic lymphoma, non-Hodgkin's lymphomas (e.g.,Burkitt's, Small Cell, and Large Cell lymphomas), Hodgkin's lymphoma,leukemia (including AML, ALL, and CML), multiple myeloma, breast cancer(e.g., triple negative breast cancer)), Acute DisseminatedEncephalomyelitis (ADEM), Acute necrotizing hemorrhagicleukoencephalitis, Addison's disease, Agammaglobulinemia, Alopeciaareata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBMnephritis, Antiphospholipid syndrome (APS), Autoimmune angioedema,Autoimmune aplastic anemia, Autoimmune dysautonomia, Autoimmunehepatitis, Autoimmune hyperlipidemia, Autoimmune immunodeficiency,Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmuneoophoritis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmunethrombocytopenic purpura (ATP), Autoimmune thyroid disease, Autoimmuneurticaria, Axonal or neuronal neuropathies, Balo disease, Behcet'sdisease, Bullous pemphigoid, Cardiomyopathy, Castleman disease, Celiacdisease, Chagas disease, Chronic fatigue syndrome, Chronic inflammatorydemyelinating polyneuropathy (CIDP), Chronic recurrent multifocalostomyelitis (CRMO), Churg-Strauss syndrome, Cicatricialpemphigoid/benign mucosal pemphigoid, Crohn's disease, Cogans syndrome,Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis,CREST disease, Essential mixed cryoglobulinemia, Demyelinatingneuropathies, Dermatitis herpetiformis, Dermatomyositis, Devic's disease(neuromyelitis optica), Discoid lupus, Dressler's syndrome,Endometriosis, Eosinophilic esophagitis, Eosinophilic fasciitis,Erythema nodosum, Experimental allergic encephalomyelitis, Evanssyndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis(temporal arteritis), Giant cell myocarditis, Glomerulonephritis,Goodpasture's syndrome, Granulomatosis with Polyangiitis (GPA) (formerlycalled Wegener's Granulomatosis), Graves' disease, Guillain-Barresyndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, Hemolyticanemia, Henoch-Schonlein purpura, Herpes gestationis,Hypogammaglobulinemia, Idiopathic thrombocytopenic purpura (ITP), IgAnephropathy, IgG4-related sclerosing disease, Immunoregulatorylipoproteins, Inclusion body myositis, Interstitial cystitis, Juvenilearthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis,Kawasaki syndrome, Lambert-Eaton syndrome, Leukocytoclastic vasculitis,Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgAdisease (LAD), Lupus (SLE), Lyme disease, chronic, Meniere's disease,Microscopic polyangiitis, Mixed connective tissue disease (MCTD),Mooren's ulcer, Mucha-Habermann disease, Multiple sclerosis, Myastheniagravis, Myositis, Narcolepsy, Neuromyelitis optica (Devic's),Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromicrheumatism, PANDAS (Pediatric Autoimmune Neuropsychiatric DisordersAssociated with Streptococcus), Paraneoplastic cerebellar degeneration,Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome,Parsonnage-Turner syndrome, Pars planitis (peripheral uveitis),Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis,Pernicious anemia, POEMS syndrome, Polyarteritis nodosa, Type I, II, &III autoimmune polyglandular syndromes, Polymyalgia rheumatica,Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomysyndrome, Progesterone dermatitis, Primary biliary cirrhosis, Primarysclerosing cholangitis, Psoriasis, Psoriatic arthritis, Idiopathicpulmonary fibrosis, Pyoderma gangrenosum, Pure red cell aplasia,Raynauds phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy,Reiter's syndrome, Relapsing polychondritis, Restless legs syndrome,Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis,Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren'ssyndrome, Sperm & testicular autoimmunity, Stiff person syndrome,Subacute bacterial endocarditis (SBE), Susac's syndrome, Sympatheticophthalmia, Takayasu's arteritis, Temporal arteritis/Giant cellarteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome,Transverse myelitis, Type 1 diabetes, Ulcerative colitis,Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis,Vesiculobullous dermatosis, Vitiligo, Wegener's granulomatosis (i.e.,Granulomatosis with Polyangiitis (GPA), traumatic brain injury,arthritis, rheumatoid arthritis, psoriatic arthritis, juvenileidiopathic arthritis, multiple sclerosis, systemic lupus erythematosus(SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitustype 1, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto'sthyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome,vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet'sdisease, Crohn's disease, ulcerative colitis, bullous pemphigoid,sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory boweldisease, Addison's disease, Vitiligo, asthma, allergic asthma, acnevulgaris, celiac disease, chronic prostatitis, inflammatory boweldisease, pelvic inflammatory disease, reperfusion injury, sarcoidosis,transplant rejection, interstitial cystitis, atherosclerosis, atopicdermatitis, Alexander's disease, Alper's disease, Alzheimer's disease,Amyotrophic lateral sclerosis, Ataxia telangiectasia, Batten disease(also known as Spielmeyer-Vogt-Sjogren-Batten disease), Bovinespongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome,Corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporaldementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease,HIV-associated dementia, Kennedy's disease, Krabbe's disease, kuru, Lewybody dementia, Machado-Joseph disease (Spinocerebellar ataxia type 3),Multiple sclerosis, Multiple System Atrophy, Narcolepsy,Neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher Disease,Pick's disease, Primary lateral sclerosis, Prion diseases, Refsum'sdisease, Sandhoffs disease, Schilder's disease, Subacute combineddegeneration of spinal cord secondary to Pernicious Anaemia,Schizophrenia, Spinocerebellar ataxia (multiple types with varyingcharacteristics), Spinal muscular atrophy, Steele-Richardson-Olszewskidisease, Tabes dorsalis, diabetes (e.g., type I or type II), obesity,metabolic syndrome, a mitochondrial disease (e.g., dysfunction ofmitochondria or aberrant mitochondrial function), fungal infection,transplant rejection, or a cardiovascular disease (e.g., congestiveheart failure; arrhythmogenic syndromes (e.g., paroxysomal tachycardia,delayed after depolarizations, ventricular tachycardia, suddentachycardia, exercise-induced arrhythmias, long QT syndromes, orbidirectional tachycardia); thromboembolic disorders (e.g., arterialcardiovascular thromboembolic disorders, venous cardiovascularthromboembolic disorders, or thromboembolic disorders in the chambers ofthe heart); atherosclerosis; restenosis; peripheral arterial disease;coronary bypass grafting surgery; carotid artery disease; arteritis;myocarditis; cardiovascular inflammation; vascular inflammation;coronary heart disease (CHD); unstable angina (UA); unstable refractoryangina; stable angina (SA); chronic stable angina; acute coronarysyndrome (ACS); myocardial infarction (first or recurrent); acutemyocardial infarction (AMI); myocardial infarction; non-Q wavemyocardial infarction; non-STE myocardial infarction; coronary arterydisease; ischemic heart disease; cardiac ischemia; ischemia; ischemicsudden death; transient ischemic attack; stroke; peripheral occlusivearterial disease; venous thrombosis; deep vein thrombosis;thrombophlebitis; arterial embolism; coronary arterial thrombosis;cerebral arterial thrombosis, cerebral embolism; kidney embolism;pulmonary embolism; thrombosis (e.g., associated with prosthetic valvesor other implants, indwelling catheters, stents, cardiopulmonary bypass,hemodialysis); thrombosis (e.g., associated with atherosclerosis,surgery, prolonged immobilization, arterial fibrillation, congenitalthrombophilia, cancer, diabetes, hormones, or pregnancy); or cardiacarrhythmias (e.g., supraventricular arrhythmias, atrial arrhythmias,atrial flutter, or atrial fibrillation).

In an aspect is provided a method of treating a disease includingadministering an effective amount of a compound as described herein. Inan aspect is provided a compound as described herein for use as amedicament (e.g., for treatment of a disease). In an aspect is provideda compound as describe herein for use in the treatment of a disease(e.g., including administering an effective amount of a compound asdescribed herein). In embodiments, the disease is cancer. Inembodiments, the disease is an autoimmune disease. In embodiments, thedisease is an inflammatory disease. In embodiments, the disease is aneurodegenerative disease. In embodiments, the disease is a metabolicdisease. In embodiments, the disease is fungal infection. Inembodiments, the disease is transplant rejection. In embodiments, thedisease is an inflammatory disease. In embodiments, the disease is acardiovascular disease. In embodiments, the disease is Cancer (e.g.,carcinomas, sarcomas, adenocarcinomas, lymphomas, leukemias, solidcancers, lymphoid cancers; cancer of the kidney, breast, lung, bladder,colon, ovarian, prostate, pancreas, stomach, brain, head and neck, skin,uterine, esophagus, liver; testicular cancer, glioma, hepatocarcinoma,lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin'slymphomas (e.g., Burkitt's, Small Cell, and Large Cell lymphomas),Hodgkin's lymphoma, leukemia (including AML, ALL, and CML), multiplemyeloma, breast cancer (e.g., triple negative breast cancer)), AcuteDisseminated Encephalomyelitis (ADEM), Acute necrotizing hemorrhagicleukoencephalitis, Addison's disease, Agammaglobulinemia, Alopeciaareata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBMnephritis, Antiphospholipid syndrome (APS), Autoimmune angioedema,Autoimmune aplastic anemia, Autoimmune dysautonomia, Autoimmunehepatitis, Autoimmune hyperlipidemia, Autoimmune immunodeficiency,Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmuneoophoritis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmunethrombocytopenic purpura (ATP), Autoimmune thyroid disease, Autoimmuneurticaria, Axonal or neuronal neuropathies, Balo disease, Behcet'sdisease, Bullous pemphigoid, Cardiomyopathy, Castleman disease, Celiacdisease, Chagas disease, Chronic fatigue syndrome, Chronic inflammatorydemyelinating polyneuropathy (CIDP), Chronic recurrent multifocalostomyelitis (CRMO), Churg-Strauss syndrome, Cicatricialpemphigoid/benign mucosal pemphigoid, Crohn's disease, Cogans syndrome,Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis,CREST disease, Essential mixed cryoglobulinemia, Demyelinatingneuropathies, Dermatitis herpetiformis, Dermatomyositis, Devic's disease(neuromyelitis optica), Discoid lupus, Dressler's syndrome,Endometriosis, Eosinophilic esophagitis, Eosinophilic fasciitis,Erythema nodosum, Experimental allergic encephalomyelitis, Evanssyndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis(temporal arteritis), Giant cell myocarditis, Glomerulonephritis,Goodpasture's syndrome, Granulomatosis with Polyangiitis (GPA) (formerlycalled Wegener's Granulomatosis), Graves' disease, Guillain-Barresyndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, Hemolyticanemia, Henoch-Schonlein purpura, Herpes gestationis,Hypogammaglobulinemia, Idiopathic thrombocytopenic purpura (ITP), IgAnephropathy, IgG4-related sclerosing disease, Immunoregulatorylipoproteins, Inclusion body myositis, Interstitial cystitis, Juvenilearthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis,Kawasaki syndrome, Lambert-Eaton syndrome, Leukocytoclastic vasculitis,Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgAdisease (LAD), Lupus (SLE), Lyme disease, chronic, Meniere's disease,Microscopic polyangiitis, Mixed connective tissue disease (MCTD),Mooren's ulcer, Mucha-Habermann disease, Multiple sclerosis, Myastheniagravis, Myositis, Narcolepsy, Neuromyelitis optica (Devic's),Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromicrheumatism, PANDAS (Pediatric Autoimmune Neuropsychiatric DisordersAssociated with Streptococcus), Paraneoplastic cerebellar degeneration,Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome,Parsonnage-Turner syndrome, Pars planitis (peripheral uveitis),Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis,Pernicious anemia, POEMS syndrome, Polyarteritis nodosa, Type I, II, &III autoimmune polyglandular syndromes, Polymyalgia rheumatica,Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomysyndrome, Progesterone dermatitis, Primary biliary cirrhosis, Primarysclerosing cholangitis, Psoriasis, Psoriatic arthritis, Idiopathicpulmonary fibrosis, Pyoderma gangrenosum, Pure red cell aplasia,Raynauds phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy,Reiter's syndrome, Relapsing polychondritis, Restless legs syndrome,Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis,Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren'ssyndrome, Sperm & testicular autoimmunity, Stiff person syndrome,Subacute bacterial endocarditis (SBE), Susac's syndrome, Sympatheticophthalmia, Takayasu's arteritis, Temporal arteritis/Giant cellarteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome,Transverse myelitis, Type 1 diabetes, Ulcerative colitis,Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis,Vesiculobullous dermatosis, Vitiligo, Wegener's granulomatosis (i.e.,Granulomatosis with Polyangiitis (GPA), traumatic brain injury,arthritis, rheumatoid arthritis, psoriatic arthritis, juvenileidiopathic arthritis, multiple sclerosis, systemic lupus erythematosus(SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitustype 1, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto'sthyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome,vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet'sdisease, Crohn's disease, ulcerative colitis, bullous pemphigoid,sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory boweldisease, Addison's disease, Vitiligo, asthma, allergic asthma, acnevulgaris, celiac disease, chronic prostatitis, inflammatory boweldisease, pelvic inflammatory disease, reperfusion injury, sarcoidosis,transplant rejection, interstitial cystitis, atherosclerosis, atopicdermatitis, Alexander's disease, Alper's disease, Alzheimer's disease,Amyotrophic lateral sclerosis, Ataxia telangiectasia, Batten disease(also known as Spielmeyer-Vogt-Sjogren-Batten disease), Bovinespongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome,Corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporaldementia, Gerstmann-Striussler-Scheinker syndrome, Huntington's disease,HIV-associated dementia, Kennedy's disease, Krabbe's disease, kuru, Lewybody dementia, Machado-Joseph disease (Spinocerebellar ataxia type 3),Multiple sclerosis, Multiple System Atrophy, Narcolepsy,Neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher Disease,Pick's disease, Primary lateral sclerosis, Prion diseases, Refsum'sdisease, Sandhoffs disease, Schilder's disease, Subacute combineddegeneration of spinal cord secondary to Pernicious Anaemia,Schizophrenia, Spinocerebellar ataxia (multiple types with varyingcharacteristics), Spinal muscular atrophy, Steele-Richardson-Olszewskidisease, Tabes dorsalis, diabetes (e.g., type I or type II), obesity,metabolic syndrome, a mitochondrial disease (e.g., dysfunction ofmitochondria or aberrant mitochondrial function), fungal infection,transplant rejection, or a cardiovascular disease (e.g., congestiveheart failure; arrhythmogenic syndromes (e.g., paroxysomal tachycardia,delayed after depolarizations, ventricular tachycardia, suddentachycardia, exercise-induced arrhythmias, long QT syndromes, orbidirectional tachycardia); thromboembolic disorders (e.g., arterialcardiovascular thromboembolic disorders, venous cardiovascularthromboembolic disorders, or thromboembolic disorders in the chambers ofthe heart); atherosclerosis; restenosis; peripheral arterial disease;coronary bypass grafting surgery; carotid artery disease; arteritis;myocarditis; cardiovascular inflammation; vascular inflammation;coronary heart disease (CHD); unstable angina (UA); unstable refractoryangina; stable angina (SA); chronic stable angina; acute coronarysyndrome (ACS); myocardial infarction (first or recurrent); acutemyocardial infarction (AMI); myocardial infarction; non-Q wavemyocardial infarction; non-STE myocardial infarction; coronary arterydisease; ischemic heart disease; cardiac ischemia; ischemia; ischemicsudden death; transient ischemic attack; stroke; peripheral occlusivearterial disease; venous thrombosis; deep vein thrombosis;thrombophlebitis; arterial embolism; coronary arterial thrombosis;cerebral arterial thrombosis, cerebral embolism; kidney embolism;pulmonary embolism; thrombosis (e.g., associated with prosthetic valvesor other implants, indwelling catheters, stents, cardiopulmonary bypass,hemodialysis); thrombosis (e.g., associated with atherosclerosis,surgery, prolonged immobilization, arterial fibrillation, congenitalthrombophilia, cancer, diabetes, hormones, or pregnancy); or cardiacarrhythmias (e.g., supraventricular arrhythmias, atrial arrhythmias,atrial flutter, or atrial fibrillation). In embodiments, the disease isa polycystic disease. In embodiments, the disease is polycystic kidneydisease. In embodiments, the disease is stenosis. In embodiments, thedisease is restenosis. In embodiments, the disease is neointimalproliferation. In embodiments, the disease is neointimal hyperplasia.

In another aspect is provided a method of treating aging in a subject inneed of such treatment, the method including administering a compound,or a pharmaceutically acceptable salt thereof, as described herein,including embodiments (e.g. a claim, embodiment, example, table, figure,or claim) to the subject.

In another aspect is provided a compound as described herein for use asa medicament. In embodiments, the medicament may be useful for treatingaging in a subject in need of such treatment. In embodiments, the usemay include administering a compound, or a pharmaceutically acceptablesalt thereof, as described herein, including embodiments (e.g. anaspect, embodiment, example, table, figure, or claim) to the subject.

In another aspect is provided a compound for use in the treatment ofaging in a subject in need of such treatment. In embodiments, the usemay include administering a compound, or a pharmaceutically acceptablesalt thereof, as described herein, including embodiments (e.g. anaspect, embodiment, example, table, figure, or claim) to the subject.

In another aspect is provided a method of extending life span orinducing longevity in a subject in need of such treatment, the methodincluding administering a compound, or a pharmaceutically acceptablesalt thereof, as described herein, including embodiments (e.g. a claim,embodiment, example, table, figure, or claim) to the subject.

In another aspect is provided a compound as described herein for use asa medicament. In embodiments, the medicament may be useful for extendinglife span or inducing longevity in a subject in need of such treatment.In embodiments, the use may include administering a compound, or apharmaceutically acceptable salt thereof, as described herein, includingembodiments (e.g. an aspect, embodiment, example, table, figure, orclaim) to the subject.

In another aspect is provided a compound for use in extending life spanor inducing longevity in a subject in need of such treatment. Inembodiments, the use may include administering a compound, or apharmaceutically acceptable salt thereof, as described herein, includingembodiments (e.g. an aspect, embodiment, example, table, figure, orclaim) to the subject.

In an aspect is provided a method of treating a polycystic disease in asubject in need of such treatment. The polycystic disease may bepolycystic kidney disease. The method includes administering to thesubject a compound described herein. The method may includeadministering to the subject a therapeutically effective amount of acompound described herein (e.g., an mTORC1 modulator (e.g., inhibitor)as described above).

In an aspect is provided a compound as described herein for use as amedicament. In embodiments, the medicament is useful for treating apolycystic disease. The polycystic disease may be polycystic kidneydisease. The use includes administering to the subject a compounddescribed herein. The use may include administering to the subject atherapeutically effective amount of a compound described herein (e.g.,an mTORC1 modulator (e.g., inhibitor) as described above).

In an aspect is provided a compound as described herein for use in thetreatment of a polycystic disease in a subject in need of suchtreatment. The polycystic disease may be polycystic kidney disease. Theuse includes administering to the subject a compound described herein.The use may include administering to the subject a therapeuticallyeffective amount of a compound described herein (e.g., an mTORC1modulator (e.g., inhibitor) as described above).

In an aspect is provided a method of treating stenosis in a subject inneed of such treatment. The stenosis may be restenosis. The methodincludes administering to the subject a compound described herein. Inembodiments the compound is administered in a drug eluting stent. Themethod may include administering to the subject a therapeuticallyeffective amount of a compound described herein (e.g., an mTORC1modulator (e.g., inhibitor) as described above).

In an aspect is provided a compound as described herein for use as amedicament. In embodiments, the medicament is useful for treatingstenosis. The stenosis may be restenosis. The use includes administeringto the subject a compound described herein. In embodiments the compoundis administered in a drug eluting stent. The use may includeadministering to the subject a therapeutically effective amount of acompound described herein (e.g., an mTORC1 modulator (e.g., inhibitor)as described above).

In an aspect is provided a compound as described herein for use in thetreatment of stenosis in a subject in need of such treatment. Thestenosis may be restenosis. The use includes administering to thesubject a compound described herein. In embodiments the compound isadministered in a drug eluting stent. The use may include administeringto the subject a therapeutically effective amount of a compounddescribed herein (e.g., an mTORC1 modulator (e.g., inhibitor) asdescribed above).

In embodiments, the disease is a disease described herein and thecompound is a compound described herein.

D. Methods of Modulating mTORC1

In another aspect is provided a method of modulating mTORC1 activity ina subject in need thereof, including administering to the subject aneffective amount of a compound as described herein, or apharmaceutically acceptable salt thereof. In embodiments, the methodincludes inhibiting mTORC1 activity. In embodiments, the method includesinhibiting mTORC1 activity and not inhibiting mTORC2 activity. Inembodiments, the method includes inhibiting mTORC1 activity more thaninhibiting mTORC2 activity. In embodiments, the method includesinhibiting mTORC1 activity at least 1.1 fold as much as inhibitingmTORC2 activity (e.g., at least 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8,1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100,200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000,6000, 7000, 8000, 9000, 10000, 10000, 20000, 30000, 40000, 50000, 60000,70000, 80000, 90000, 100000, 100000, 200000, 300000, 400000, 500000,600000, 700000, 800000, 900000, or 1000000 fold).

In some embodiments, the mTORC1 is in a cell. In some embodiments, thecell is a mammalian cell, such as a human cell. The cell may be isolatedin vitro, form part of a tissue in vitro, or may form part of anorganism.

Modulating mTORC1 activity includes directly or indirectly modulatingone or more functions of mTORC1 and/or one or more downstream effects ofmTORC1. In other words, the function or effect of mTORC1 is alteredcompared to the function or effect of mTORC1 when the modulator (e.g.,compound as described herein) is not present.

In embodiments, the mTORC1 modulator (e.g., compound as describedherein, including in embodiments) is an mTORC1 inhibitor that decreasesone or more of: activation of mTORC1, co-factor binding by mTORC1,co-factor binding by mTOR, and/or phosphorylation of 4EBP1. Inembodiments, the mTORC1 modulator (e.g., compound as described herein,including in embodiments) is an mTORC1 inhibitor that decreasesphosphorylation of S6 and/or S6K. In another embodiment, an effectiveamount of mTORC1 inhibitor is an amount sufficient to decrease mTORC1activity in a cell (e.g., in a subject) to reduce cell proliferationrelative to the amount of cell proliferation in the absence of mTORC1inhibitor. In another embodiment, an effective amount of mTORC1modulator (e.g., inhibitor) is an amount sufficient to increase celldeath (e.g., apoptosis).

In embodiments, the compound reduces activation of eIF4E. Inembodiments, the compound inhibits phosphorylation of 4E-BP1. Inembodiments, the compound does not reduce phosphorylation of Akt. Inembodiments, the compound does not reduce phosphorylation of Akt-473 ora residue corresponding to Akt-473. In embodiments, the compound doesnot cause hyperglycemia.

In an embodiment, modulating mTORC1 activity includes direct binding ofthe mTORC1 modulator to mTOR. In another embodiment, modulating mTORC1activity is accomplished indirectly.

E. ADDITIONAL EMBODIMENTS

1. A compound comprising a monovalent active site mTOR inhibitorcovalently bound to a monovalent rapamycin or a monovalent rapamycinanalog.

2. The compound of embodiment 1, wherein a divalent linker binds themonovalent active site mTOR inhibitor to the monovalent rapamycin or themonovalent rapamycin analog.

3. The compound of embodiment 2, wherein the divalent linker is at least5 Å in length.

4. The compound of embodiment 2, wherein the divalent linker is at least17 Å in length.

5. The compound of embodiment 2, wherein the divalent linker is at least32 Å in length.

6. The compound of one of embodiments 2 to 5, wherein the compoundcomprises the divalent linker covalently bound to the monovalent activesite mTOR inhibitor and the monovalent rapamycin or monovalent rapamycinanalog.

7. The compound of one of embodiments 1 to 6, having the formula:

wherein,L¹ is the divalent linker; R³ is hydrogen, oxo, halogen, —CX₃, —CN,—SO_(n)R¹⁰, —SO_(v)NR⁷R⁸, —NHNR⁷R⁸, —ONR⁷R⁸, —NHC═(O)NHNR⁷R⁸,—NHC═(O)NR⁷R⁸,—NHC═(O)NR⁷R⁸, —N(O)_(m), —NR⁷R⁸, —C(O)R⁹, —C(O)—OR⁹, —C(O)NR⁷R⁸, —OR¹⁰,—NR⁷SO₂R¹⁰, —NR⁷C═(O)R⁹, —NR⁷C(O)OR⁹, —NR⁷OR⁹, —OCX₃, —OCHX₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁷, R⁸, R⁹, and R¹⁰ areindependently hydrogen,halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCHF₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁷ and R⁸ substituents bondedto the same nitrogen atom may optionally be joined to form a substitutedor unsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; W¹ is N or CH; m and v are independently 1 or 2; n isindependently an integer from 0 to 4; and X is independently —Cl, —Br,—I, or —F.8. The compound of embodiment 7, having the formula:

9. The compound of one of embodiments 7 to 8, wherein R³ is substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.10. The compound of one of embodiments 7 to 8, wherein R³ is substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.11. The compound of one of embodiments 7 to 8, wherein R³ is substitutedor unsubstituted aryl or substituted or unsubstituted heteroaryl.12. The compound of one of embodiments 7 to 8, wherein R³ is substitutedor unsubstituted fused ring aryl or substituted or unsubstituted fusedring heteroaryl.13. The compound of one of embodiments 7 to 8, wherein R³ is substitutedor unsubstituted fused ring heteroaryl.14. The compound of one of embodiments 7 to 8, wherein R³ is substitutedfused ring heteroaryl.15. The compound of one of embodiments 7 to 8, wherein R³ is substitutedbenzoxazolyl, substituted pyrimidinyl, substituted thiophenyl,substituted furanyl, substituted indolyl, substituted benzoxadiazolyl,substituted benzodioxolyl, substituted benzodioxanyl, substitutedthianaphthanyl, substituted pyrrolopyridinyl, substituted indazolyl,substituted quinolinyl, substituted quinoxalinyl, substitutedpyridopyrazinyl, substituted quinazolinonyl, substitutedbenzoisoxazolyl, substituted imidazopyridinyl, substituted benzofuranyl,substituted benzothiophenyl, substituted phenyl, substituted naphthyl,substituted biphenyl, substituted pyrrolyl, substituted pyrazolyl,substituted imidazolyl, substituted pyrazinyl, substituted oxazolyl,substituted isoxazolyl, substituted thiazolyl, substituted furylthienyl,substituted pyridyl, substituted pyrimidyl, substituted benzothiazolyl,substituted purinyl, substituted benzimidazolyl, substitutedisoquinolyl, substituted thiadiazolyl, substituted oxadiazolyl,substituted pyrrolyl, substituted diazolyl, substituted triazolyl,substituted tetrazolyl, substituted benzothiadiazolyl, substitutedisothiazolyl, substituted pyrazolopyrimidinyl, substitutedpyrrolopyrimidinyl, substituted benzotriazolyl, or substituted quinolyl.16. The compound of one of embodiments 7 to 15, wherein L¹ isL²-L³-L⁴-L⁵; L² is connected directly to the monovalent rapamycin or themonovalent rapamycin analog; L² is substituted or unsubstitutedalkylene, substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene; L³ is a bond, substituted orunsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene; L⁴ is a bond, substituted orunsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene; and L⁵ is a bond,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, or substituted or unsubstituted heteroarylene.17. The compound of embodiment 16, wherein L² is substituted orunsubstituted C₁-C₂₀ alkylene, substituted or unsubstituted 2 to 20membered heteroalkylene, substituted or unsubstituted C₃-C₈cycloalkylene, substituted or unsubstituted 3 to 8 memberedheterocycloalkylene, substituted or unsubstituted C₆-C₁₀ arylene, orsubstituted or unsubstituted 5 to 10 membered heteroarylene; L³ is abond, substituted or unsubstituted C₁-C₂₀ alkylene, substituted orunsubstituted 2 to 20 membered heteroalkylene, substituted orunsubstituted C₃-C₈ cycloalkylene, substituted or unsubstituted 3 to 8membered heterocycloalkylene, substituted or unsubstituted C₆-C₁₀arylene, or substituted or unsubstituted 5 to 10 membered heteroarylene;L⁴ is a bond, substituted or unsubstituted C₁-C₂₀ alkylene, substitutedor unsubstituted 2 to 20 membered heteroalkylene, substituted orunsubstituted C₃-C₈ cycloalkylene, substituted or unsubstituted 3 to 8membered heterocycloalkylene, substituted or unsubstituted C₆-C₁₀arylene, or substituted or unsubstituted 5 to 10 membered heteroarylene;and L⁵ is a bond, substituted or unsubstituted C₁-C₂₀ alkylene,substituted or unsubstituted 2 to 20 membered heteroalkylene,substituted or unsubstituted C₃-C₈ cycloalkylene, substituted orunsubstituted 3 to 8 membered heterocycloalkylene, substituted orunsubstituted C₆-C₁₀ arylene, or substituted or unsubstituted 5 to 10membered heteroarylene.18. The compound of embodiment 16, wherein L² is substituted orunsubstituted 3 to 8 membered heteroalkylene; L³ is a substituted orunsubstituted 5 to 10 membered heteroarylene; L⁴ is a substituted orunsubstituted 2 to 12 membered heteroalkylene; and L⁵ is a substitutedor unsubstituted 2 to 12 membered heteroalkylene.19. The compound of one of embodiments 1 to 18, wherein the compound isan mTORC1 specific inhibitor.20. A pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and a compound of one of embodiments 1 to 19.21. A method of inhibiting the activity of mTORC1 in a patient, themethod comprising administering an effective amount of a compound of oneof embodiments 1 to 19, or a pharmaceutically acceptable salt thereof,to the patient.22. The method of embodiment 21, wherein the method comprises inhibitingthe level of activity of mTORC1 at least 1.1, 1.2, 1.3, 1.4, 1.5, 1.6,1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80,90, 100, 1000, 10000, or 100000-times the inhibition of the level ofactivity of TORC2.23. A method of treating a disease associated with aberrant mTORC1activity in a patient in need of such treatment, the method comprisingadministering a therapeutically effective amount of a compound of one ofembodiments 1 to 19, or a pharmaceutically acceptable salt thereof, tothe patient.24. The method of embodiment 23, wherein the disease is cancer.25. A method of treating a disease in a subject, the method comprisingadministering a compound of one of embodiments 1 to 19, or apharmaceutically acceptable salt thereof, to the subject, wherein thedisease is a cancer, autoimmune disease, inflammatory disease, metabolicdisease, neurodegenerative disease, fungal infection, transplantrejection, aging, stenosis, neointimal proliferation, cardiovasculardisease, or polycystic disease.26. The method of embodiment 25, wherein the disease is cancer.27. The method of embodiment 5, wherein the disease is an autoimmunedisease.28. The method of embodiment 25, wherein the disease is an inflammatorydisease.29. The method of embodiment 25, wherein the disease is a metabolicdisease.30. The method of embodiment 25, wherein the disease is aneurodegenerative disease.31. The method of embodiment 25, wherein the disease is a fungalinfection.32. The method of embodiment 25, wherein the disease is transplantrejection.33. The method of embodiment 25, wherein the disease is aging.34. The method of embodiment 25, wherein the disease is stenosis.35. The method of embodiment 34, wherein the stenosis is restenosis.36. The method of embodiment 25, wherein the disease is neointimalproliferation.37. The method of embodiment 25, wherein the disease is a polycysticdisease.38. The method of embodiment 37, wherein the polycystic disease ispolycystic kidney disease.39. The method of embodiment 25, wherein the compound, or apharmaceutically acceptable salt thereof, is administered in adrug-eluting stent.

F. EXAMPLES A. Example 1

The action of MLN0128 on TORC2 is not thought to be necessary for itsanti-cancer activity. This has been analyzed in a genetically engineeredmouse model of Akt-driven lymphomagenesis¹⁰. A non-phosphorylatablemutant of 4E-BP1 which is constitutively able to inhibit eIF4E, blocksAkt-driven lymphomagenesis, suggesting that this single substrate ofmTOR is sufficient to support cancer cell growth and survival. In someanimals harboring the constitutively active Akt and constitutivelyactive 4E-BP1, some tumors which still express the 4E-BP1 mutant(4EBP1^(M)). Presumably, another pathway has been activated whichbypasses the block imposed by 4EBP1^(M). These cells offer a genetictest of the mechanism of action of the asTORi class of inhibitors. Ifthe action of asTORi on cells is mediated by 4E-BP1 phosphorylation,then there should be no effect of the drug when added to the cells whichbypass 4EBP1^(M). The asTORi, PP242 has no significant effect in suchcells (FIG. 1), confirming that the cell killing effects of asTORi ismediated in large part, if not completely, by phosphorylation of 4E-BP1which leads to activation of eIF4E¹⁰.

This assessment of the mechanism of action of various mTOR inhibitorssuggests that inhibition of 4E-BP1 phosphorylation is essential forpotent anti-cancer activity. Furthermore, the inhibition of TORC2,leading to dephosphorylation of Akt-473 is the key contributor to thedose limiting toxicity of hyperglycemia in clinical trials of asTORisuch as MLN0128, and is dispensable for tumor cell killing.

An emerging desirable feature of kinase inhibitor drugs is the abilityto inhibit kinase activity following drug washout¹⁶. The EGFR/HER2inhibitor Lapatinib, exhibits slow-off kinetics from EGFR which isthought to be caused by a required conformational change in the kinaseto allow drug to be released. Regardless of the mechanism, it is thoughtthat kinase inhibitors with slow off kinetics will be better able torobustly inhibit kinase signaling in a tumor. Rather than requiring highdrug levels in the blood stream 24 hr/day, such slow off drugs maydemonstrate better target coverage than the more common rapidlydissociating kinase inhibitors.

B. Example 2

Design and Generation of a Third Class of mTOR inhibitor-“Rapa-Link”. Inthe last year, the crystal structure of a portion of mTOR was solved byPavletich and coworkers¹⁷. This structure, in conjunction with a muchearlier structure of Rapamycin bound to the isolated FRB and FKBPproteins¹⁸ provides an opportunity to develop a completely new class ofmTOR inhibitors. By utilizing the TORC1 selective nature of Rapamycin,and linking Rapamycin to (in a way that does not disrupt Rapamycin'sbinding to FKBP12 or the FRB domain of mTOR) an asTORi (e.g., MLN0128)we predicted that a new type of pharmacological agent for targeting mTORcould be developed (FIGS. 2A and 2B). This approach to design of an mTORinhibitor has never been proposed previously and provides a novelpharmacological means of blocking mTOR signaling. The key aspect of thisdesign is to use Rapamycin to “deliver” an asTORi (e.g., MLN0128) to theactive site of mTORC1, effectively blocking both pS6 and 4E-BP1. Thesecond aspect of the design would be that linking Rapamycin to an asTORi(e.g., MLN0128) would result in binding to FKBP12 in cells, and in thislarge complex of an asTORi (e.g., MLN0128)-Rapa/FKBP12, an asTORi (e.g.,MLN0128) would be diminished in its ability to bind to mTORC2 and thuswould have reduced effects on Akt S473.

The basis for selective inhibition of mTORC1 by the new Rapamycin-asTORi(e.g., MLN0128) conjugate molecules (Rapa-Link) and their comparison toRapamycin and asTORi (e.g., MLN0128) is shown in FIGS. 3A and 3B.

C. Example 3

In order to determine the optimal regiochemistry and cross-linker lengthfor tethering Rapamycin to an asTORi (e.g., MLN0128), two independentcrystal structures of mTOR (PDB:4JT5)¹⁷ and FRB:FKBP12:Rapamycin(1FAP)¹⁸ were overlayed, using the common FRB domain contained in bothstructures (FIG. 4A).

To design the hybrid compound, the tethering positions to Rapamycin wasdesigned in a way to minimize disruption of its binding to the FKBP12protein and FRB domain of mTOR. Similarly, the linking group to anasTORi (e.g., MLN0128) was designed to avoid disrupting the active siteinhibitor binding to catalytic domain of mTOR. Analysis of the Rapamycincocrystal structure (1FAP)¹⁸ revealed that the hydroxyl group at the C40position of rapamycin is exposed to solvent region and is orientedtoward the active site of mTOR (FIG. 4A). For an asTORi (e.g., MLN0128)a tethering position was selected based on co-crystal structures of mTORusing PP242 as the model ATP site ligand, which is highly related toMLN0128 (FIG. 4A). MLN0128 was selected as the asTORi for this work,because 1) MLN0128 is a clinical candidate which has good mTORselectivity and possesses sufficient drug-like properties; 2) ourstructure-activity relationship (SAR) knowledge ofpyrazolo[3,4-d]pyrimidine analogs is applicable to rational designs ofcross-linkers.

In order to design the proper cross-linker (L), we attempted to convertthe distance between Rapamycin and the asTORi into a discrete number ofheavy atoms using the modeling program, Molecular Operating Environment(MOE) (2013.0801). We first evaluated methylene cross-linkers, L:(CH₂)_(n), with the length from n=10 to n=40 which tethers rapamycinwith a substructure of PP242 (precursor of MLN0128) and determined thatthe long linker (n≥27) would be preferable (FIG. 4B). According to theresults of this computational calculation, we designed the followingcompounds (M-1071, M-1111, M-3059 and M-1115)—see FIG. 4B for chemicalstructures.

D. Example 4

Chemical Synthesis. We designed Rapa-Link inhibitors (M-1071, M-1111,M-3059, M-1115, etc.) possessing a drug-like cross-linker (polyethyleneglycol based) which would provide a rapid means for coupling the twohalves of the molecule (azide/alkyne cyclization). We considered thestructural complexity of rapamycin and its cost, and decided to apply aconvergent synthetic route (Scheme 1-A). Hence, we synthesized propargylethyleneglycol introduced rapamycin (III-A) as a precursor (Scheme 3).For the asTORi (Scheme 2), we prepared two types of compounds (II-c)with an attachment “A”; 1) Type A has an amino group at the terminalposition; 2) Type B has a carboxylate at the terminal position. Thoseterminal functional groups will be used to connect the active siteinhibitor to the cross-linker by amide formation reaction. Among variouskinds of cross-linkers, we selected the polyethylene glycol (PEG) linkersince it is found in a number of pharmaceuticals²⁰. We used azide PEGlinkers to connect asTORi (IIc-A) followed by triazole formationreaction with propargyl derivative of Rapamycin (III-A) (Scheme 1-A). Byusing the key intermediates, we also synthesized a negative controlcompound (M-1115) which is designed to have linker predicted to be tooshort to allow optimal dual binding to mTOR (FIG. 4B).

TABLE 3 Rapa-Link Molecules Length of Compound Structure Salt linker(heavy atoms) M-1071

2HCO₂H 39 M-1111

2HCO₂H 36 M-3059

2HCO₂H 27 M-1115

2HCO₂H 11 Control: (M-1062)

Free base N/A

E. Example 5

Abbreviations used in syntheses descriptions. AcOH: acetic acid, DME:1,2-dimethoxyethane, DMF: N,N-dimethylformamide, DMSO:dimethylsulfoxide, dPEG: discrete poly-(ethylene glycol), EDCI:1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, ESI: electrosprayionization, EtOAc: ethyl acetate, HOBt: 1-hydroxybenzotriazole, HPLC:high performance liquid chromatography, HR-MS: high resolution massspectroscopy, LC-MS: liquid chromatography-mass spectrometry, LTQ-FT:linear trap quadrupole-Fourier transform, MeOH: methanol, NHS:N-hydroxysuccinimide, NMR: nuclear magnetic resonance, RP-HPLC: reversephase-high performance liquid chromatography, THF: tetrahydrofuran, TLC:thin layer chromatography, TMS: tetramethylsilane.

Starting materials, reagents, and solvents for reactions were of reagentgrade and were used as purchased. TLC was carried out using MerckKieselgel 60, 63-200 mesh, F254 plates, or Fuji Silysia Chemical Ltd.,100-200 mesh, NH plates. Chromatographic purification was carried outusing silica gel (Merck, 70-230 mesh) or basic silica gel (Fuji SilysiaChemical Ltd., DM1020, 100-200 mesh). RP-HPLC was carried out on aWaters Binary Gradient Module 2545 system equipped with an AgilentZorbax 300-SB C18 column (5 μm, 4.6×250 mm) for analytical mode or aWaters XBridge Prep C₁₈ column (5 μm, 30×250 mm) for preparative mode.The column was eluted with CH₃CN/water/0.1% formic acid (gradient mode),which was monitored by Waters Photodiode Array Detector 2998 (UV atA=254 nm). Yields were not optimized.

¹H NMR spectra for intermediates were recorded on a Varian Innova (400MHz) spectrometer. ¹H NMR spectra, ¹H—¹H COSY, HSQC, and HMBC spectrafor final compounds were recorded on a Bruker Avance (800 MHz)spectrometer. ¹³C NMR spectra were recorded on a Bruker Avance (500 MHz)spectrometer (500 MHz for ¹H, 126 MHz for ¹³C). ¹H chemical shifts arereported in δ (ppm) as s (singlet), d (doublet), t (triplet), q(quartet), dd (double doublet), m (multiplet) or br s (broad singlet)and are referenced to TMS as an internal standard. LC-MS (ESI-MS)spectra were recorded with a Waters 2695 separations module using aWaters ACQUITY UPLC BEH C18 1.7 μm column and were used to confirm ≥95%purity of each compound. Mobile phase A was 0.1% formic acid inultrapure water. Mobile phase B was 0.1% formic acid in acetonitrile,which was increased linearly from 5% to 95% over 1.8 min and 95% overthe next 0.3 min (flow rate: 0.6 mL/min). HR-MS analysis was conductedby QB3/Chemistry Mass Spectrometry Facility at UC Berkeley. Samples wereanalyzed by electrospray ionization with a mass measuring accuracy of 5ppm using the LTQ-FT instrument.

Preparation of Compound 6 (M-1062

Preparation of 2-(prop-2-yn-1-yloxy)ethanol 3. To a cooledethane-1,2-diol (1) (150 mL) was slowly added NaH oil dispersion (43.2g) over 1 h at −30° C. The mixture was stirred at ambient temperaturefor additional 1 h. To the reaction mixture was slowly added 9.2 Mpropargyl bromide (2) solution in toluene (45.47 g) over 30 min undercooling bath (−10° C.). The mixture was stirred at 50° C. for 60 h. Itwas then partitioned between EtOAc (400 mL) and water (200 mL). Theaqueous layer was separated and extracted with EtOAc (200 mL). Theorganic layers were combined, washed with brine (100 mL) and dried overanhydrous MgSO₄. The insoluble was filtered and the filtrate wasevaporated in vacuo. The crude material was purified by silica gelcolumn chromatography (silica gel: 800 g, solvent: hexanes (2 L)followed by 50% EtOAc in hexanes (4 L)). The desired fractions werecombined and evaporated in vacuo to give the titled compound (9.63 g,31%) as a yellow oil. This material was used for the next reactionwithout further purification.

¹H NMR (400 MHz, CDCl₃) δ 4.19-4.22 (2H, m), 3.73-3.79 (2H, m),3.63-3.67 (2H, m), 2.45 (1H, t, J=2.4 Hz), 1.96 (1H, t, J=6.0 Hz).

Preparation of 2-(prop-2-yn-1-yloxy)ethyl trifluoromethanesulfonate 4.To a solution of 2-(prop-2-yn-1-yloxy)ethanol (3) (1.50 g, 15.0 mmol) inCH₂Cl₂ (20 mL) was added 2,6-lutidine (2.44 mL, 21.0 mmol) followed bytrifluoromethanesulfonic anhydride (3.15 mL, 18.7 mmol) at −50° C. underargon atmosphere. The mixture was stirred at −10° C. for 2 h. It wasthen partitioned between 50% EtOAc in hexanes (150 mL) and brine (15mL). The organic layer was separated, washed with brine (15 mL) anddried over anhydrous MgSO₄. The insoluble was filtered and the filtratewas evaporated in vacuo. The crude material was purified by silica gelcolumn chromatography (silica gel: 50 g, solvent 10% EtOAc in hexanes(500 mL)). The desired fractions were combined and evaporated in vacuoto give the titled compound (2.49 g, 72%) as a dark brown oil. Thismaterial was used for the next reaction without further purification.

¹H NMR (400 MHz, CDCl₃) 54.64-4.66 (2H, m), 4.22-4.25 (2H, m), 3.85-3.88(2H, m), 2.48-2.49 (1H, m).

Preparation of 40-O-(2-(prop-2-yn-1-yloxy)ethyl)-rapamycin 6 (M-1062).To a solution of rapamycin (5) (652 mg, 0.714 mmol) in CHCl₃ (1.5 mL)were added a solution of 2-(prop-2-yn-1-yloxy)ethyltrifluoromethanesulfonate (4) (1.25 g, 5.35 mmol) in CHCl₃ (1.5 mL) andN,N-diisopropyl-N-ethylamine (6.2 mL, 35.7 mmol) at −10° C. under argonatmosphere. The mixture was stirred at 60° C. for 30 min. An additionalamount of 2-(prop-2-yn-1-yloxy)ethyl trifluoromethanesulfonate (4) (1.25g, 5.35 mmol) in CHCl₃ (1.5 mL) was added. The mixture was stirred at60° C. for additional 1 h. It was then cooled and partitioned betweenEtOAc (100 mL) and water (50 mL). The organic layer was washed withwater (50 mL) and brine (2×25 mL), successively, and dried overanhydrous MgSO₄. The insoluble was filtered off and the filtrate wasevaporated in vacuo. The crude material was purified by silica gelcolumn chromatography (silica gel: 25 g, solvent: 20-80% EtOAc inhexanes). Desired fractions were combined and evaporated in vacuo. Theobtained material was dissolved into 50% CH₃CN in water and lyophilizedto give the titled compound (277 mg, 28%) as a colorless amorphouspowder.

HR-MS (ESI−) Calcd for C₅₆H₈₄O₁₄N (M−H)⁻ 994.5897. Found 994.5885 (Δ−1.24 ppm).

TABLE 4 NMR Analysis of M-1062 M-1062

δ ¹³C Major Atom Atom Type δ ¹H Major (3:1) (3:1) HMBC C to H ¹H-¹H COSY1 C═O 169.2 2 N/A 2 CH 5.28 (br d, 4.8 Hz) 51.2 4a, 6a 3a,b 3 CH₂ a:2.35 (m) 27.1 2 3b, 2, 4b b: 1.74 (m) 3a, 2, 4b 4 CH₂ a: 1.77 (m) 20.7 24b, 3a, 5b b: 1.47 (m) 4a, 3a 5 CH₂ a: 1.74 (m) 25.3 3a, 6a 5b, 6b b:1.49 (m) 5a, 4a, 6a,b 6 CH₂ a: 3.57 (m) 44.2 2, 4a,b 6b, 5b b: 3.44 (m)6a, 5a,b 8 C═O N/A 166.8 2, 6a N/A 9 C═O N/A 192.5 n.d. N/A 10 O—C—OHN/A 98.5 12, 43 N/A 11 CH 1.97 (m) 33.7 12, 43 12, 13a, 43 12 CH₂ 1.59(2H, m) 27.3 43 11, 13b 13 CH₂ a: 1.61 (m) 31.3 12, 15a 11, 13b b: 1.31(m) 13a, 12, 14 14 CH—OC 3.87 (m) 67.2 12, 15a 13b, 15a, b 15 CH₂ a:1.85 (m) 38.8 16 15b, 14, 16 b: 1.52 (m) 15a, 14, 16 16 CH—OCH₃ 3.66 (m)84.4 15a, 18, 50 15a, b 17 —C═ N/A 135.5 15a, 19, 44 N/A 18 CH═C 5.96(d, 9.6 Hz) 129.7 16, 20, 44 19 19 CH═C 6.38 (dd, 14.4, 10.8 126.4 20,21, 44 18, 20 Hz) 20 CH═C 6.35 (dd, 16.6, 10.2 133.7 18, 19, 21, 19, 21Hz) 22 21 CH═C 6.14 (dd, 15.2, 10.2 130.2 19 20, 22 Hz) 22 CH═C 5.55(dd, 14.8, 9.2 140.2 20, 24b, 45 21, 23 Hz) 23 CH 2.33 (m) 35.2 21, 22,24a, 22, 24a, 45 45 24 CH₂ a: 1.49 (m) 40.2 22, 25, 45, 24b, 23 b: 1.21(m) 46 24a, 25 25 CH 2.74 (dd, 17.0, 5.8) 41.4 24a,b, 46 24b, 46 26 C═ON/A 215.7 n.d. N/A 27 CH—OCH₃ 3.71 (m) 84.8 28, 51 28 28 CH—OH 4.18 (m)77.3 27, 30, 47 27 29 C═C N/A 136.1 28, 31, 47 N/A 30 CH═C 5.41 (d, 10.0Hz) 126.8 28, 31, 47, 31 48 31 CH 3.34 (m) 46.6 30, 48 30, 48 32 C═O N/A208.2 31, 33a,b, N/A 48 33 CH₂ a: 2.73 (m) 40.8 n.d. 33b, 34 b: 2.59 (m)33a, 34 34 CH—OCO 5.16 (dd, 10.0, 5.8 75.7 33a,b, 49 33a,b, 35 Hz) 35 CH1.95 (m) 33.2 33a,b, 34, 36a,b, 36a,b, 49 49 36 CH₂ a: 1.19 (m) 38.3 34,38b, 49 36b, 35, 37 b: 1.11 (m) 36a, 35 37 CH 1.33 (m) 33.1 36a,b, 36a,38b, 38a,b, 42b 42b 38 CH₂ a: 2.03 (m) 36.3 36a,b 38b, 39 b: 0.71 (m)38a, 37, 39 39 CH—OCH₃ 3.06 (m) 83.2 38a,b,40, 52 38a,b, 40 40 CH—O—3.13 (m) 83.3 38a,b, 39, 39, 41b 52, 53 41 CH₂ a: 2.05 (m) 30.1 42b 41bb: 1.26 (m) 41a, 40, 42b 42 CH₂ a: 1.69 (m) 31.8 36a,b, 38a,b 42b b:0.92 (m) 42a, 37, 41b 43 11-CH₃ 0.94 (3H, d, 6.4 Hz) 16.3 11, 12 11 4417-CH₃ 1.65 (3H, s) 10.2 16, 18 n.d. 45 23-CH₃ 1.05 (3H, d, 6.4 Hz) 21.622, 24a 23 46 25-CH₃ 0.99 (3H, d, 6.4 Hz) 13.8 24a, b, 25 25 47 29-CH₃1.74 (3H, s) 13.1 28, 30 n.d. 48 31-CH₃ 1.10 (3H, d, 6.8 Hz) 16.0 30, 3131 49 35-CH₃ 0.91 (3H, d, 6.8 Hz) 16.9 36b 35 50 16-OCH₃ 3.14 (3H, s)55.9 16 n.d. 51 27-OCH₃ 3.34 (3H, s) 59.5 27 n.d. 52 39-OCH₃ 3.46 (3H,s) 58.0 39 n.d. 53 40-OCH₂— 3.72-3.79 (2H, m) 69.3 54, 40 54 54 —CH₂—O—3.64-3.71 (2H, m) 69.6 53, 55 53, 55 55 —O—CH₂ 4.20-4.22 (2H, m) 58.654, 57 54, 57 56 —C≡ N/A 79.8 55, 57 N/A 57 ≡CH 2.41 (t, 2.2 Hz) 74.4 5555 OH protons were not identified.

Preparation of Compound 11a (M-1115

Preparation of1-(4-chlorobutyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine 8a. To asuspension of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (7) (2.11 g,8.08 mmol) (prepared by a similar method to that described in NatureChemical Biology, 2008, 691-699) in DMF (25 mL) was added NaH oildispersion (485 mg, 12.1 mmol) at 4° C. The mixture was stirred at 4° C.for 30 min. To the reaction mixture was added 1-bromo-4-chlorobutane(1.45 g, 8.46 mmol) at 4° C. The mixture was stirred at room temperaturefor 14 h. To the mixture was added water (25 mL) at room temperature.The mixture was cooled to 4° C. and stirred for 30 min. The resultingprecipitate was collected by filtration. The obtained crude material waspurified by silica gel column chromatography (silica gel: 40 g, solvent:20-100% EtOAc in hexanes, 0-30% MeOH in EtOAc, and then DMF). Desiredfractions were combined and evaporated in vacuo. The obtained DMFsolution (ca.100 mL) including desired material was diluted with water(150 mL). The resulting suspension was stirred at 4° C. for 30 min. Theprecipitate was collected by filtration. Drying the solid gave thetitled compound (2.01 g, 71%) as a pale beige solid.

¹H NMR (400 MHz, DMSO-d₆) δ8.20 (1H, s), 4.30 (2H, t, J=6.8 Hz), 3.65(2H, t, J=6.8 Hz), 1.85-1.95 (2H, m), 1.61-1.70 (2H, m), NH₂ protonswere not identified.

LC-MS (ESI) m/z=352.05 (M+H)⁺.

Preparation of5-(4-amino-1-(4-chlorobutyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine9a. To a bi-phasic suspension of1-(4-chlorobutyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (8a) (703mg, 2.00 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine(780 mg, 3.00 mmol) (prepared by a similar method to that described inWO2010/051042A1), and saturated aqueous Na₂CO₃ solution (10 mL) in DME(30 mL) and water (10 mL) was addedtetrakis(triphenylphosphine)palladium (0) (232 mg, 200 μmol) at roomtemperature under argon atmosphere. The mixture was stirred at 110° C.for 3 h. It was then cooled and partitioned between EtOAc (200 mL) andwater (100 mL). The aqueous layer was separated and extracted with EtOAc(100 mL). The organic layers were combined, washed with brine (50 mL)and dried over anhydrous MgSO₄. The insoluble was filtered off and thefiltrate was concentrated in vacuo. The crude material was purified bysilica gel column chromatography (basic silica gel: 25 g, solvent: 20%MeOH in EtOAc (100 mL)). The desired fractions were combined and theobtained solid was triturated with EtOAc (50 mL) for 30 min. Theprecipitate was collected by filtration. Drying the solid gave thetitled compound (445 mg, 62%) as a pale beige solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (1H, s), 7.53 (2H, s), 7.47 (1H, d,J=8.0 Hz), 7.41 (1H, br s), 7.25 (1H, dd, J=8.4, 1.2 Hz), 4.37 (2H, t,J=6.8 Hz), 3.67 (2H, t, J=6.8 Hz), 1.93-2.02 (2H, m), 1.67-1.76 (2H, m),NH₂ protons were not identified.

LC-MS (ESI) m/z=358.20 (M+H)⁺.

Preparation of5-(4-amino-1-(4-azidobutyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine10a. To a solution of5-(4-amino-1-(4-chlorobutyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine(9a) (140 mg, 0.391 mmol) in DMF (3 mL) were added sodium azide (33.0mg, 0.507 mmol) and potassium iodide (12.0 mg, 72.3 μmol) at roomtemperature. The mixture was stirred at 70° C. for 6 h. It was thencooled and partitioned between EtOAc (100 mL) and water (20 mL). Theaqueous layer was separated and extracted with EtOAc (50 mL). Theorganic layers were combined, washed with brine (20 mL), and dried overanhydrous MgSO₄. The insoluble was filtered off and the filtrate wasevaporated in vacuo. The obtained material was triturated with EtOAc (5mL) for 15 min. The precipitate was collected by filtration. Drying thesolid gave the titled compound (121 mg, 85%) as a pale beige powder.

¹H NMR (400 MHz, DMSO-d₆) δ8.24 (1H, s), 7.53 (2H, s), 7.47 (1H, d,J=8.0 Hz), 7.41 (1H, d, J=1.6 Hz), 7.24 (1H, dd, J=8.0, 1.6 Hz), 4.37(2H, t, J=6.8 Hz), 3.36 (2H, t, J=6.8 Hz), 1.86-1.95 (2H, m), 1.48-1.57(2H, m), NH₂ protons were not identified.

LC-MS (ESI) m/z=365.21 (M+H)*.

Preparation of40-O-(2-((1-(4-(4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)butyl)-1H-1,2,3-triazol-4-yl)methoxy)ethyl)-rapamycin11a (M-1115) To a solution of5-(4-amino-1-(4-azidobutyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo[d]oxazol-2-amine(10a) (16 mg, 43.9 μmol) in a mixed solvent of MeOH (8 mL) and CH₂Cl₂ (4mL) was added 40-O-(2-(prop-2-yn-1-yloxy)ethyl)-rapamycin (6) (32.5 mg,32.6 μmol). To the mixture were added 1 M aqueous CuSO₄ solution (100μL, 100 μmol) and 1 M aqueous sodium ascorbate solution (100 μL, 100μmol). The mixture was stirred at room temperature for 4 h. It was thenconcentrated in vacuo. The crude material was partitioned between 20%THF in EtOAc (20 mL) and water (5 mL). The aqueous layer was separatedand extracted with 20% THF in EtOAc (10 mL). The organic layers werecombined, washed with brine (20 mL), and dried over anhydrous MgSO₄. Themixture was dissolved into DMSO (4 mL) and 50% CH₃CN in water (4 mL) andthe solution was passed through a pad of Celite (#545). The filtrate waspurified by preparative RP-HPLC (20-95% CH₃CN in water containing 0.1%formic acid). The desired fractions were combined and lyophilized togive formic acid salt of the titled compound (9.1 mg, 19%) as acolorless amorphous powder.

LC-MS (ESI−) m/z=1358.47 (M−H)⁻.

HR-MS (ESI−) Calcd for C₇₂H₁₀₀O₁₅N₁₁ (M−H)⁻ 1358.7406, Found 1358.7372(Δ −2.49 ppm)

TABLE 5 NMR analysis of M-1115 M-1115

Atom Atom Type δ¹H Major (3:1) δ¹³C Major (3:1) HMBC C to H ¹H—¹H COSY 1 C═O N/A 169.3  2 N/A  2 CH 5.28 (d, 5.6 Hz)  51.3  4a, 6a  3b  3 CH₂a: 2.33 (m)  27.0  2, 5a  3b, 4a,b   b: 1.73 (m)  3a, 2, 4a,b  4 CH₂ a:1.78 (m)  20.7  2, 6a,b  4b, 3a,b, 5a,b   b: 1.48 (m)    4a, 3a,b, 5a,b 5 CH₂ a: 1.72 (m)  25.3  3a, 4a, 6a,b  5b, 4a,b   b: 1.46 (m)    5a,4a,b, 6a,b  6 CH₂ a: 3.54 (m)  44.2  2, 4a, 5b  6b, 5b   b: 3.41 (m) 6a, 5b  8 C═O N/A 166.7  2, 6a,b N/A  9 C═O N/A 193.3 n.d. N/A 10O—C—OH N/A  98.6 11, 12, 43 N/A 11 CH 2.01 (m)  34.0 43 12, 43 12 CH₂1.60 (2H, m)  27.2 11, 43 11, 13a,b 13 CH₂ a: 1.66 (m)  31.3 12, 15a13b, 12 b: 1.30 (m)   13a, 12, 14 14 CH—OC 3.91 (m)  67.2 12, 15a, 1613b, 15a,b 15 CH₂ a: 1.87 (m)  39.2 16 15b, 14, 16 b: 1.44 (m)   15a,14, 16 16 CH—OCH₃ 3.65 (m)  84.1 15a,b, 18, 50 15a,b 17 —C═ N/A 136.215a, 19, 44 N/A 18 CH═C 5.98 (d, 10.8 Hz) 129.1 16, 20, 44 19 19 CH═C6.38 (dd, 14.2, 10.8 Hz) 126.6 20, 21 18, 20 20 CH═C 6.30 (dd, 14.4,10.2 Hz) 133.3 18, 19, 21, 22 19, 21 21 CH═C 6.13 (dd, 14.8, 10.4 Hz)130.3 19, 20 20, 22 22 CH═C 5.53 (dd, 14.8, 8.8 Hz) 139.7 20, 24a,b, 4521, 23 23 CH 2.32 (m)  35.0 21, 22, 24a,b, 45 22, 24a, 45 24 CH₂ a: 1.43(m)  40.3 22, 25, 45, 46 24b, 23 b: 1.20 (m)   24a, 25 25 CH 2.65 (m) 41.6 24a,b, 46 24b, 46 26 C═O N/A 214.6 n.d. N/A 27 CH—OCH₃ 3.84 (d,4.2 Hz)  85.0 28, 51 28 28 CH—OH 4.24 (d, 4.0 Hz)  76.8 27, 30, 47 27 29C═C N/A 135.9 28, 30, 47 N/A 30 CH═C 5.45 (d, 9.6 Hz) 126.2 28, 31, 47,48 31 31 CH 3.30 (m)  46.6 30, 48 30, 48 32 C═O N/A 208.3 31, 33a,b, 48N/A 33 CH₂ a: 2.68 (m)  40.5 n.d. 33b, 34 b: 2.55 (m)   33a, 34 34CH—OCO 5.16 (m)  75.6 33a,b, 36a,b, 49 33a,b, 35 35 CH 1.91 (m)  33.333a,b, 36b, 49 34, 36b, 49 36 CH₂ a: 1.16 (m)  38.5 38b, 49 36b, 37 b:1.07 (m)   36a, 35 37 CH 1.32 (m)  33.0 36b, 38a,b, 42b 36a, 38b, 42a,b38 CH₂ a: 1.99 (m)  36.4 36a,b 38b, 39 b: 0.69 (m)   38a, 37, 39 39CH—OCH₃ 3.02 (m)  83.0 38a,b, 40, 52 38a,b, 40 40 CH—O— 3.09 (m)  83.138a,b, 39, 52, 53 39, 41a,b 41 CH₂ a: 2.00 (m)  30.0 42b 41b, 40, 42a,bb: 1.22 (m)   41a, 40, 42b 42 CH₂ a: 1.64 (m)  31.6 36a,b, 42b, 37, 41ab: 0.88 (m)   38a,b 42a, 37, 41a,b 43 11-CH₃ 0.95 (3H, d, 6.6 Hz)  16.211, 12 11 44 17-CH₃ 1.66 (3H, s)  10.2 16, 18 n.d. 45 23-CH₃ 1.05 (3H,d, 6.6 Hz)  21.4 22, 24a,b 23 46 25-CH₃ 0.98 (3H, d, 6.4 Hz)  13.424a,b, 25 25 47 29-CH₃ 1.79 (3H, s)  13.7 28, 30 n.d. 48 31-CH₃ 1.07(3H, d, 6.6 Hz)  15.9 30, 31 31 49 35-CH₃ 0.89 (3H, d, 6.6 Hz)  15.7 34,36b 35 50 16-OCH₃ 3.14 (3H, s)  55.9 16 n.d. 51 27-OCH₃ 3.33 (3H, s) 58.9 27 n.d. 52 39-OCH₃ 3.40 (3H, s)  57.8 39 n.d. 53 40-OCH₂ 3.72 (2H,m)  69.2 40, 54 54 54 —CH—O— 3.64 (2H, m)  70.2 53, 55 53 55—OCH₂triazo1e 4.67 (2H, s)  64.7 54 57 56 —C═ N/A 145.4 55, 57 N/A 57═CH 7.55 (s) 122.4 55, 57 55 58 PP—C N/A 143.7 68 N/A 59 PP—C N/A  98.561 N/A 60 PP—C—NH₂ N/A 158.0 61 N/A 61 PP—CH 8.35 (s) 155.8 n.d. n.d. 62PP—C N/A 154.4 61, 72 N/A 63 BO—C—NH₂ N/A 162.8 n.d. N/A 64 BO—C N/A144.8 65, 67 N/A 65 BO—CH 7.63 (s) 116.2 67 67 66 BO—C N/A 129.2 68 N/A67 BO—CH 7.40 (br d, 7.8 Hz) 121.8 65 65, 68 68 BO—CH 7.42 (d, 7.8 Hz)109.8 65 67 69 BO—C N/A 149.2 65, 67 N/A 72 N—CH₂ 4.49 (2H, m)  46.1 73,74 73 73 CH₂ 2.01 (2H, m)  26.6 72, 74, 75 72, 74 74 CH₂ 1.95 (2H, m) 27.4 72, 73, 75 73, 75 75 CH₂ 4.41 (2H, t, 6.8 Hz)  49.6 57, 73, 74 74PPstands for pyrazolo[3,4-d]pyrimidine and BO stands for benzo[d]oxazoleOHprotons and NHx protons were not identified.

Preparation of Compound 11b (M-1071; Example 1

Preparation of tert-butyl(4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)butyl)carbamate 8b.To a suspension of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (7) (2.11g, 8.08 mmol) in DMF (25 mL) was added NaH oil dispersion (485 mg, 12.1mmol) at 4° C. The mixture was stirred at 4° C. for 30 min. To thereaction mixture was added tert-butyl (4-bromobutyl)carbamate (2.50 g,8.92 mmol) in DMF (5 mL) at 4° C. The mixture was stirred at roomtemperature for 14 h. To the mixture was added water (100 mL) at roomtemperature. The mixture was cooled to 4° C. and stirred for 30 min. Theresulting precipitate was collected by filtration. Drying the solid gavethe titled compound (3.01 g, 86%) as a colorless powder.

¹H NMR (400 MHz, DMSO-d₆) δ8.33 (1H, s), 5.86 (2H, br s), 4.61 (1H, brs), 4.39 (2H, t, J=7.2 Hz), 3.05-3.25 (2H, br s), 1.90-1.98 (2H, m),1.44-1.55 (2H, m), 1.43 (9H, s).

LC-MS (ESI) m/z=433.09 (M+H)⁺.

Preparation of tert-butyl(4-(4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)butyl)carbamate9b. To a bi-phasic suspension of tert-butyl(4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)butyl)carbamate (8b)(435 mg, 1.00 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine(390 mg, 1.50 mmol), and Na₂CO₃ (530 mg, 5.00 mmol) in DME (10 mL) andwater (5 mL) was added tetrakis(triphenylphosphine)palladium (0) (116mg, 100 μmol) at room temperature under argon atmosphere. The mixturewas stirred at 110° C. for 3 h. It was then cooled and partitionedbetween EtOAc (90 mL) and water (30 mL). The aqueous layer was separatedand extracted with EtOAc (2×30 mL). The organic layers were combined,washed with brine (2×30 mL) and dried over anhydrous MgSO₄. Theinsoluble was filtered off and the filtrate was concentrated in vacuo.The crude material was purified by silica gel column chromatography(silica gel: 75 g, solvent: 50% EtOAc in hexanes (400 mL) followed by20% MeOH in EtOAc (800 mL)). The desired fractions were combined andevaporated in vacuo. The obtained solid was recrystallized fromMeOH/water to give the titled compound (332 mg, 76%) as a colorlesssolid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.23 (1H, s), 7.52 (2H, s), 7.46 (1H, d,J=8.0 Hz), 7.41 (1H, s), 7.23 (1H, dd, J=8.0, 1.2 Hz), 6.79 (1H, t,J=5.6 Hz), 4.32 (2H, t, J=5.6 Hz), 3.26-3.33 (2H, m), 2.88-2.96 (2H, m),1.77-1.87 (2H, m), 1.35 (9H, s), NH₂ protons were not identified.

LC-MS (ESI) m/z=439.28 (M+H)⁺.

Preparation ofN-(4-(4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)butyl)-1-azido-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-amide10b. To a cooled liquid of TFA (3 mL) was added tert-butyl(4-(4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)butyl)carbamate(9b) (300 mg, 0.68 mmol) at 4° C. The mixture was stirred at ambienttemperature for 1 h. It was then evaporated in vacuo. The oily residuewas triturated with Et₂O for 10 min. The supernatant was removed andthen the precipitate was triturated with 2 M hydrochloride in Et₂Osolution (3 mL) for 30 min. The precipitate was collected by filtrationunder argon atmosphere. Drying the solid gave the salt of Boc-cleavedcompound (362 mg). The obtained material (136 mg) was dissolved into DMF(4 mL). To the mixture was added triethylamine (146 μL, 1.05 mmol)followed by a solution of azide-dPEG8-NHS ester (Catalog number 10503,Quanta BioDesign, Ltd., Powell, Ohio USA) (200 mg, 0.35 mmol) in DMF (4mL) under argon atmosphere. The mixture was stirred at room temperaturefor 13 h. It was then evaporated in vacuo. The residue was partitionedbetween 10% THF in EtOAc (100 mL) and brine (20 mL). The aqueous layerwas separated and extracted with EtOAc (50 mL). The organic layers werecombined and dried over anhydrous MgSO₄. The insoluble was filtered offand the filtrate was evaporated in vacuo. The resulting crude materialwas purified by silica gel column chromatography (silica gel: 25 g,2-25% MeOH in CH₂Cl₂). Desired fractions were combined and evaporated invacuo to give the titled compound (145 mg, 72% in 2 steps) as acolorless wax.

¹H NMR (400 MHz, CDCl₃) δ 8.36 (1H, s), 7.63 (1H, s), 7.38-7.40 (2H, m),6.74 (1H, br s), 5.73 (1H, s), 4.46-4.48 (2H, m), 3.58-3.67 (31H, m),3.39-3.41 (2H, m), 3.28-3.30 (2H, m), 2.45 (2H, br s), 2.01 (2H, br s),1.59 (2H, br s), 4H protons were not identified.

LC-MS (ESI) m/z=786.34 (M−H)⁻.

Preparation of40-O-(2-((1-(32-(4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-27-oxo-3,6,9,12,15,18,21,24-octaoxa-28-azadotriacontyl)-1H-1,2,3-triazol-4-yl)methoxy)ethyl)-rapamycin11b (M-1071). To a solution ofN-(4-(4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)butyl)-1-azido-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-amide(10b) (25.6 mg, 32.5 μmol) in MeOH (9 mL) was added40-O-(2-(prop-2-yn-1-yloxy)ethyl)-rapamycin (6) (32.5 mg, 32.6 μmol). Tothe mixture were added 1 M aqueous CuSO₄ solution (120 μL, 120 μmol) and1 M aqueous sodium ascorbate solution (60.0 μL, 60.0 μmol). The mixturewas stirred at room temperature for 1 h. An additional amount of (10b)(10.5 mg, 13.3 μmol) was added. The mixture was stirred for additional 2h. It was then concentrated in vacuo. The crude material was partitionedbetween 20% THF in EtOAc (50 mL) and water (20 mL). The aqueous layerwas separated and extracted with 20% THF in EtOAc (50 mL). The combinedorganic layer was dried over anhydrous MgSO₄. The mixture was passedthrough a pad of Celite (#545) using EtOAc. The filtrate wasconcentrated in vacuo and the crude material was purified by preparativeRP-HPLC (20-95% CH₃CN in water containing 0.1% formic acid). The desiredfractions were combined and lyophilized to give formic acid salt of thetitled compound (13.3 mg, 22%) as a colorless amorphous powder.

LC-MS (ESI−) m/z=1781.79 (M−H)⁻.

HR-MS (ESI−) Calcd for C₉₁H₁₃₇O₂₄N₁₂ (M−H)⁻ 1781.9874, Found 1781.9826(Δ −2.70 ppm).

TABLE 6 NMR analysis of M-1071 M-1071

Atom Atom Type δ¹H Major (3:1) δ¹³C Major (3:1) HMBC C to H ¹H—¹H COSY 1 C═O N/A 169.3  2 N/A  2 CH 5.28 (d, 5.6 Hz)  51.3  3a,b, 6a  3b  3CH₂ a: 2.34 (m)  27.1  2, 5a  3b, 4b   b: 1.76(m)    3a,2  4 CH₂ a: 1.78(m)  20.7  2, 6a,b  4b, 5a,b   b: 1.47 (m)      4a, 3a, 5a,b  5 CH₂ a:1.74 (m)  25.3  3a, 4b  5b, 4a,b   b: 1.47 (m)      5a, 4a,b, 6b  6 CH₂a: 3.56 (m)  44.2  2, 4a,b, 5b  6b   b: 3.43 (m)    6a, 5b  8 C═O N/A166.7  2, 6a N/A  9 C═O N/A 196.3 n.d. N/A 10 O—C—OH N/A  98.5 11, 12,43 N/A 11 CH 2.00 (m)  33.8 12, 43 12, 43 12 CH₂ 1.60 (2H, m)  27.2 4311, 13a,b 13 CH₂ a: 1.64 (m)  31.2 12, 15a 13b, 12 b: 1.31 (m)   13a,12, 14 14 CH—OC 3.88 (m)  67.2 12, 15a 13b, 15a,b 15 CH₂ a: 1.85 (m) 38.9 16 15b, 14, 16 b: 1.49 (m)   15a, 14, 16 16 CH—OCH₃ 3.65 (m)  84.315a, 18, 44, 50 15a,b 17 —C═ N/A 135.7 15a, 44 N/A 18 CH═C 5.98 (d, 11.2Hz) 129.4 44 19 19 CH═C 6.39 (dd, 14.8, 10.8 Hz) 126.5 20, 21 18, 20 20CH═C 6.31 (dd, 14.8, 10.4 Hz) 133.5 18, 19, 21, 22 19, 21 21 CH═C 6.14(dd, 14.8, 10.4 Hz) 130.2 19 20, 22 22 CH═C 5.55 (dd, 15.4, 8.6 Hz)140.0 20, 24a,b, 45 21, 23 23 CH 2.32 (m)  35.0 21, 22, 24a,b, 25, 4522, 24a, 45 24 CH₂ a: 1.47 (m)  40.3 22, 25, 45, 46 24b, 23 b: 1.21 (m)  24a, 25 25 CH 2.70 (m)  41.5 24a,b, 46 24b, 46 26 C═O N/A n.d. (>210)n.d. N/A 27 CH—OCH₃ 3.78 (m)  84.9 28, 51 28 28 CH—OH 4.20 (d, 4.8 Hz) 77.1 27, 30, 47 27 29 —C═ N/A 136.0 28, 31, 47 N/A 30 CH═C 5.42 (d,10.4 Hz) 126.5 28, 31, 47, 48 31 31 CH 3.29 (d, 10.4 Hz)  46.6 30, 4830, 48 32 C═O N/A 208.3 30, 31, 33a,b, 48 N/A 33 CH₂ a: 2.70 (m)  40.7n.d. 33b, 34 b: 2.58 (m)   33a, 34 34 CH—OCO 5.16 (dd, 10.4, 6.4 Hz) 75.6 33a,b, 49 33a,b, 35 35 CH 1.93 (m)  33.2 33a,b, 49 34, 36a,b, 4936 CH₂ a: 1.17 (m)  38.4 34, 38b, 49 36b, 35, 37 b: 1.09 (m)   36a, 35,37 37 CH 1.33 (m)  33.0 36a,b, 38a,b, 36a,b, 38b,   42a,b 42a,b 38 CH₂a: 2.02 (m)  36.3 36a,b, 42a 38b, 39 b: 0.69 (m)   38a, 37, 39 39CH—OCH₃ 3.05 (m)  83.0 38a,b, 40, 52 38a,b, 40 40 CH—O— 3.11 (m)  83.138a,b, 39, 52, 53 39, 41a,b 41 CH₂ a: 2.01 (m)  30.0 42b. 41b, 40, 42bb: 1.24 (m)   41a, 40, 42b 42 CH₂ a: 1.66 (m)  31.7 36b, 38a,b 42b, 37b: 0.89 (m)   42a, 37, 41a,b 43 11-CH₃ 0.95 (3H, d, 6.7 Hz)  16.2 11, 1211 44 17-CH₃ 1.65 (3H, s)  10.2 16, 18 n.d. 45 23-CH₃ 1.05 (3H, d, 6.4Hz)  21.5 22, 24a,b 23 46 25-CH₃ 0.99 (3H, d, 6.5 Hz)  13.6 24a,b, 25 2547 29-CH₃ 1.76 (3H, s)  13.4 28, 30 n.d. 48 31-CH₃ 1.09 (3H, d, 6.7 Hz) 16.0 30, 31 31 49 35-CH₃ 0.90 (3H, d, 6.8 Hz)  15.8 36a,b 35 50 16-OCH₃3.13 (3H, s)  55.9 16 n.d. 51 27-OCH₃ 3.33 (3H, s)  59.2 27 n.d. 5239-OCH₃ 3.43 (3H, s)  57.8 39 n.d. 53 40-OCH₂ 3.72 (2H, m)  69.2 40, 5454 54 —CH₂—O— 3.67 (2H, m)  70.2 53, 55 53 55 —OCH₂triazole 4.68 (2H, s) 64.6 54 n.d. 56 —C═ N/A 145.0 55, 57 N/A 57 ═CH 7.76 (s) 123.8 55, 95n.d. 58 PP—C N/A 144.5 65, 67, 68 N/A 59 PP—C N/A  98.5 61 N/A 60PP—C—NH₂ N/A 157.5 n.d. N/A 61 PP—CH 8.36 (s) 155.5 n.d. n.d. 62 PP—CN/A 154.1 61, 72 N/A 63 BO—C—NH₂ N/A 162.8 n.d. N/A 64 BO—C N/A 144.265, 68 N/A 65 BO—CH 7.62 (s) 116.3 67, 68 67 66 BO—C N/A 129.1 68 N/A 67BO—CH 7.38 (dd, 8.4, 1.4 Hz) 121.6 65 65, 68 68 BO—CH 7.40 (d, 8.4 Hz)109.6 65, 67 67 69 BO—C N/A 149.3 65, 67, 68 N/A 72 N—CH₂ 4.47 (2H, t,6.8 Hz)  46.6 73, 74 73 73 CH₂ 2.01 (2H, m)  27.2 72, 74, 75 72, 74 74CH₂ 1.58 (2H, m)  26.5 72, 73, 75 73, 75 75 CH₂—NHCO 3.30 (2H, m)  38.973, 74, 76 74 76 NH 6.77 (t, 4.8 Hz) N/A N/A n.d. 77 CO N/A 171.6 75,76, 78, 79 N/A 78 CH₂ 2.44 (2H, t, 5.8 Hz)  37.0 79 79 79 CH₂ 3.69 (2H,t, 5.8 Hz)  67.4 78 78 80-93 O—(CH₂CH₂—O)₇ 3.54-3.64 (28H, m)  70.3-70.6multi multi- 94 OCH₂ 3.87 (2H, t, 4.8 Hz)  69.5 95 95 95 CH₂-triazole4.54 (2H, t, 4.8 Hz)  50.2 94 94 PPstands for pyrazolo[3,4-d]pyrimidineand BO stands for benzo[d]oxazole and NHx protons OHprotons were notidentified.

Preparation of Compound 11c (M-1111; Example 2

Preparation of5-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pentanoic acid 8c. Toa suspension of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (7) (2.11 g,8.08 mmol) in DMF (25 mL) was added NaH oil dispersion (485 mg, 12.1mmol) at 4° C. The mixture was stirred at 4° C. for 30 min. To thereaction mixture was added methyl 5-bromopentanoate (1.79 g, 8.90 mmol)in DMF (5 mL) at 4° C. The mixture was stirred at room temperature for108 h. It was then partitioned between EtOAc (200 mL) and water (100mL). The aqueous layer was separated and extracted with EtOAc (100 mL).The organic layers were combined, washed with brine (50 mL), and driedover anhydrous MgSO₄. The insoluble was filtered off and the filtratewas evaporated in vacuo. The obtained material was triturated with 20%EtOAc in hexanes (100 mL) for 15 min. The resulting precipitate wascollected by filtration. Drying the solid gave the titled compound (1.94g, 64%) as a pale beige powder.

¹H NMR (400 MHz, DMSO-d₆) S8.20 (1H, s), 4.27 (2H, t, J=6.8 Hz), 3.56(3H, s), 2.32 (2H, t, J=7.6 Hz), 1.74-1.84 (2H, m), 1.40-1.50 (2H, m),2H protons were not identified.

LC-MS (ESI) m/z=376.14 (M+H)⁺.

Preparation of5-(4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pentanoicacid 9c. To a bi-phasic suspension of5-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pentanoic acid (8c)(375 mg, 1.00 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine(390 mg, 1.50 mmol), and saturated aqueous Na₂CO₃ solution (2.5 mL) inDME (10 mL) and water (2.5 mL) was addedtetrakis(triphenylphosphine)palladium (0) (116 mg, 100 μmol) at roomtemperature under argon atmosphere. The mixture was stirred at 110° C.for 3 h. The reaction mixture was cooled to 60° C. and diluted with MeOH(10 mL) and THF (10 mL). To the reaction mixture was added 4 M aqueousLiOH solution (5 mL). The mixture was stirred at 60° C. for additional 2h. It was then cooled and acidified using AcOH to adjust pH to be 3-4.The mixture was partitioned between EtOAc (200 mL) and water (10 mL).The organic layer was washed with brine (20 mL) and dried over anhydrousMgSO₄. The insoluble was filtered off and the filtrate was concentratedin vacuo. The crude material was purified by silica gel columnchromatography (silica gel: 25 g, solvent: 2-30% MeOH in CH₂Cl₂). Thedesired fractions were combined and evaporated in vacuo. The obtainedsolid was triturated with 20% EtOAc in hexanes. The resultingprecipitate was collected by filtration. Drying the solid gave thetitled compound (207 mg, 56%) as a pale pink powder.

¹H NMR (400 MHz, DMSO-d₆) δ 12.00 (1H, s), 8.24 (11H, s), 7.52 (2H, s),7.46 (1H, d, J=8.0 Hz), 7.41 (1H, d, J=1.6 Hz), 7.24 (1H, dd, J=8.0, 1.6Hz), 4.33 (2H, t, J=6.8 Hz), 2.25 (2H, t, J=7.2 Hz), 1.82-1.91 (2H, m),1.44-1.53 (2H, m), 2H protons were not identified.

LC-MS (ESI) m/z=368.22 (M+H)⁺.

Preparation of5-(4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-N-(23-azido-3,6,9,12,15,18,21-heptaoxatricosyl)pentanamide10c. To a solution of5-(4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pentanoicacid (9c) (170 mg, 0.46 mmol) in DMF (4 mL) was added triethylamine (193μL, 1.39 mmol) followed by azide-dPEG7-amine (Catalog number 10523,Quanta BioDesign, Ltd., Powell, Ohio USA) (219 mg, 0.56 mmol), EDCI (133mg, 0.69 mmol), and HOBt (93.6 mg, 0.693 mmol). The mixture was stirredat room temperature for 6 h and then stirred at 40° C. for 13 h. It wasthen partitioned between EtOAc (100 mL) and water (50 mL). The aqueouslayer was separated and extracted with EtOAc (100 mL). The organiclayers were combined, washed with brine (20 mL), and dried overanhydrous MgSO₄. The insoluble was filtered off and the filtrate wasevaporated in vacuo. The resulting crude material was purified by silicagel column chromatography (silica gel: 25 g, 2-25% MeOH in CH₂Cl₂).Desired fractions were combined and evaporated in vacuo to give thetitled compound (286 mg, 83%) as a pale brown wax. This material wasused for the next reaction without further purification.

LC-MS (ESI) m/z=744.32 (M+H)⁺.

Preparation of40-O-(2-((1-(29-(4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-25-oxo-3,6,9,12,15,18,21-heptaoxa-24-azanonacosyl)-1H-1,2,3-triazol-4-yl)methoxy)ethyl)-rapamycin11c (M-1111). To a solution of5-(4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-N-(23-azido-3,6,9,12,15,18,21-heptaoxatricosyl)pentanamide(10c) (32.0 mg, 43.0 μmol) in MeOH (5 mL) and THF (1 mL) was added40-O-(2-(prop-2-yn-1-yloxy)ethyl)-rapamycin (6) (32.5 mg, 32.6 μmol). Tothe mixture were added 1 M aqueous CuSO₄ solution (100 μL, 100 μmol) and1 M aqueous sodium ascorbate solution (50.0 μL, 50.0 μmol). The mixturewas stirred at room temperature for 2 h. It was then concentrated invacuo. After removing the insoluble material by filtration through a padof silica gel, the crude material was partitioned between 20% THF inEtOAc (50 mL) and water (5 mL). The organic layer was evaporated invacuo. The resulting crude material was purified by preparative RP-HPLC(20-95% CH₃CN in water containing 0.1% formic acid). The desiredfractions were combined and lyophilized to give formic acid salt of thetitled compound (7.6 mg, 13%) as a colorless amorphous powder.

LC-MS (ESI−) m/z=1737.69 (M−H)⁻

HR-MS (ESI−) Calcd for C₈₉H₁₃₃O₂₃N₁₂ (M−H)⁻ 1737.9612, Found 1737.9561(Δ −2.94 ppm).

TABLE 7 NMR analysis of M-1111 M-1111

Atom Atom Type δ¹H Major (3:1) δ¹³C Major (3:1) HMBC C to H ¹H—¹H COSY 1 C═O N/A 169.3  2 N/A  2 CH 5.27 (d, 4.8 Hz)  51.3  4a, 6a 3b  3 CH₂a: 2.33 (m)  27.1  2 3b, 4a,b   b: 1.74 (m)     3a, 2, 4a,b  4 CH₂ a:1.78 (m)  20.7  2, 6a 4b, 3a,b, 5a,b   b: 1.46 (m)     4a, 3a,b, 5a,b  5CH₂ a: 1.73 (m)  25.3  3a, 6a 5b, 4a,b, 6a,b   b: 1.45 (m)     5a, 4a,b,6a,b  6 CH₂ a: 3.54 (m)  44.2  2, 4a,b 6b, 5a,b   b: 3.41 (m)   6a, 5a,b 8 C═O N/A 166.8  2, 6a N/A  9 C═O N/A 197.2 n.d. N/A 10 O—C—OH N/A 98.5 11, 12, 43 N/A 11 CH 1.99 (m)  33.9 12, 43 12, 13a, 43 12 CH₂ 1.60(m)  27.2 43 11, 13b 13 CH₂ a: 1.63 (m)  31.2 12, 15a. 13b, 11 b: 1.32(m)   13a, 12, 14 14 CH—OC 3.88 (m)  67.2 12, 15a, 16 13b, 15a,b 15 CH₂a: 1.85 (m)  39.0 16 15b, 14, 16 b: 1.47 (m) 15a, 14, 16 16 CH—OCH₃ 3.66(m)  84.3 15a, 18, 44, 50 15a,b 17 —C═ N/A 135.9 15a, 19, 44 N/A 18 CH═C5.97 (d, 10.4 Hz) 129.4 20, 44 19 19 CH═C 6.38 (dd, 14.4, 11.2 Hz) 126.518, 20, 21, 22, 44 18, 20 20 CH═C 6.30 (dd, 14.4, 10.4 Hz) 133.5 18, 19,21,22 19, 21 21 CH═C 6.13 (dd, 15.2, 10.4 Hz) 130.2 19, 20 20, 22 22CH═C 5.54 (dd, 15.2, 8.8 Hz) 140.0 20, 24a,b, 45 21, 23 23 CH 2.32 (m) 35.0 21, 22, 24a,b, 25, 45 22, 24a, 45 24 CH₂ a: 1.46 (m)  40.3 22, 25,45, 46 24b, 23 b: 1.20 (m)   24a, 25 25 CH 2.69 (m)  41.5 24a,b, 45, 4624b, 46 26 C═O N/A 213.4 n.d. N/A 27 CH—OCH₃ 3.78 (d, 5.6 Hz)  84.9 28,51 28 28 CH—OH 4.20 (d, 4.8 Hz)  77.0 27, 30, 47 27 29 —C═ N/A 136.0 28,30, 31, 47 N/A 30 CH═C 5.43 (d, 10.4 Hz) 126.5 28, 31, 47, 48 31 31 CH3.32 (m)  46.6 30, 48 30, 48 32 C═O N/A 208.3 30, 31, 33a,b, 48 N/A 33CH₂ a: 2.69 (m)  40.6 n.d. 33b, 34 b: 2.57 (m)   33a, 34 34 CH—OCO 5.15(dd, 10.4, 5.6 Hz)  75.6 33a,b, 49 33a,b, 35 35 CH 1.92 (m)  33.2 33a,b,36a,b, 49 34, 36a,b, 49 36 CH₂ a: 1.16 (m)  38.4 38b, 49 36b, 35, 37 b:1.08 (m)   36a, 35, 37 37 CH 1.32 (m)  33.0 36a,b, 38a,b, 42b 36a,b,38b, 42a,b 38 CH₂ a: 2.01 (m)  36.3 36a,b 38b, 39 b: 0.70 (m)   38a, 3739 CH—OCH₃ 3.05 (m)  83.0 38a,b, 40, 52 38a, 41a 40 CH—O— 3.11 (m)  83.138a,b, 39, 52 41b 41 CH₂ a: 2.01 (m)  30.0 42b 41b, 39, 42a b: 1.23 (m)  41a, 40, 42b 42 CH₂ a: 1.65 (m)  31.7 36a,b, 38a,b 42b, 37, 41a b:0.90 (m)   42a, 37, 41b 43 11-CH₃ 0.94 (3H, d, 6.4 Hz)  16.2 11, 12 1144 17-CH₃ 1.65 (3H, s)  10.2 16, 18 n.d. 45 23-CH₃ 1.05 (3H, d, 7.2 Hz) 21.5 22, 23, 24a,b 23 46 25-CH₃ 0.98 (3H, d, 6.4 Hz)  13.6 24a,b, 25 2547 29-CH₃ 1.75 (3H, s)  13.4 28, 30 n.d. 48 31-CH₃ 1.09 (3H, d, 6.4 Hz) 16.0 30, 31 31 49 35-CH₃ 0.90 (3H, d, 6.4 Hz)  15.8 34, 36a,b 35 5016-OCH₃ 3.14 (s)  55.9 16 n.d. 51 27-OCH₃ 3.33 (s)  59.2 27 n.d. 5239-OCH₃ 3.43 (s)  57.8 39 n.d. 53 40-OCH₂ 3.74 (2H, m)  69.2 40, 54 5454 —CH₂—O— 3.67 (2H, m)  70.2 53, 55 53 55 —OCH₂triazole 4.68 (2H, s) 64.6 54 57 56 —C═ N/A 145.0 55, 57 N/A 57 ═CH 7.76 (s) 123.8 55, 93 5558 PP—C N/A 144.4 65, 67, 68 N/A 59 PP—C N/A  98.4 61 N/A 60 PP—C—NH₂N/A 157.9 61 N/A 61 PP—CH 8.36 (s) 155.8 n.d. n.d. 62 PP—C N/A 154.3 61,72 N/A 63 BO—C—NH₂ N/A 162.8 n.d. N/A 64 BO—C N/A 144.0 65, 68 N/A 65BO—CH 7.62 (s) 116.3 67,68 67 66 BO—C N/A 129.3 68 N/A 67 BO—CH 7.38 (d,8.0 Hz) 121.7 65 65, 68 68 BO—CH 7.40 (d, 8.0 Hz) 109.6 65, 67 67 69BO—C N/A 149.2 65, 67, 68 N/A 72 N—CH₂ 4.45 (2H, t, 6.8 Hz)  46.5 73, 7473 73 CH₂ 2.01 (2H, m)  29.1 72, 74, 75 72, 74 74 CH₂ 1.70 (2H, m)  22.872, 73, 75 73, 75 75 CH₂—CO 2.27 (2H, t, 7.6 Hz)  35.8 73, 74 74 76 CON/A 172.8 74, 75, 78 N/A 77 NH 6.55 (br) N/A N/A N/A 78 CH₂ 3.41 (2H, t,5.0 Hz)  39.2 79 79 79 CH₂ 3.51 (2H, t, 5.0 Hz)  70.0 78 78 80-91O—(CH₂CH₂O)₆ 3.54-3.64 (24H, m)  70.2-70.6 multi multi 92 OCH₂ 3.87 (2H,t, 5.2 Hz)  69.5 93 93 93 CH₂-triazole 4.53 (2H, t, 5.2 Hz)  50.2 92 92PPstands for pyrazolo[3,4-d]pyrimidine and BO stands for benzo[d]oxazoleand NHx protons OHprotons were not identified.

Preparation of compound 11d (M-3059; Example 3).40-O-(2-((1-(20-(4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-15-oxo-3,6,9,12-tetraoxa-16-azaicosyl)-1H-1,2,3-triazol-4-yl)methoxy)ethyl)-rapamycinlid was synthesized by a similar method to that described in thepreparation of compound 11b (M-1071).

Formic acid salt of the titled compound (41.6 mg; colorless amorphouspowder)

LC-MS (ESI−) m/z=1606.18 (M−H)⁻

HR-MS (ESI+) Calcd for C₈₃H₁₂₂O₂₀N₁₂Na (M+Na)⁺ 1629.8791, Found1629.8791 (A 0.03 ppm).

TABLE 8 NMR analysis of M-3059 M-3059

Atom Atom Type δ 1H Major (3:1) δ 13C Major (3:1) HMBC C to H 1H—1H COSY 1 C═O N/A 169.3  2 N/A  2 CH 5.28 (d, 5.5 Hz)  51.3  3a,b, 6a  3b  3CH₂ a: 2.33 (m)  27.1  2, 5a  3b, 4b   b: 1.76 (m)      3a, 2  4 CH₂ a:1.77 (m)  20.7  2, 6a,b  4b, 5a,b   b: 1.47 (m)      4a, 3a, 5a,b  5 CH₂a: 1.73 (m)  25.3  3a, 4a,b, 6a  5b, 4a,b   b: 1.47 (m)      5a, 4a,b,6b  6 CH₂ a: 3.56 (m)  44.2  2, 4a,b, 5b  6b   b: 3.42 (m)    6a, 5b  8C═O N/A 166.7  2, 6a N/A  9 C═O N/A 193.4 11 N/A 10 O—C—OH N/A  98.6 11,12, 43 N/A 11 CH 2.02 (m)  33.9 12, 43 12, 43 12 CH₂ 1.61 (2H, m)  27.243 11, 13a,b 13 CH₂ a: 1.66 (m)  31.2 12, 15a 13b, 12 b: 1.31 (m)   13a,12, 14 14 CH—OC 3.90 (m)  67.2 12, 15a 13b, 15a,b 15 CH₂ a: 1.88 (m) 38.9 16 15b, 14, 16 b: 1.46 (m)   15a, 14, 16 16 CH—OCH₃ 3.59 (m)  84.315a, 18, 44, 50 15a,b 17 —C═ N/A 136.0 15a, 44 N/A 18 CH═C 5.96 (d, 11.3Hz) 129.2 44, 20 19, 44 19 CH═C 6.39 (dd, 15.0, 11.0 Hz) 126.6 20, 2118, 20 20 CH═C 6.30 (dd, 14.8, 10.5 Hz) 133.4 18, 19, 21, 22 19, 21 21CH═C 6.14 (dd, 15.3, 10.5 Hz) 130.3 19, 20 20, 22 22 CH═C 5.53 (dd,15.1, 8.8 Hz) 139.8 20, 24a,b, 45 21, 23 23 CH 2.33 (m)  35.0 21, 22,24a,b, 45 22, 24a, 45 24 CH₂ a: 1.45 (m)  40.3 22, 25, 45, 46 24b, 23 b:1.22 (m)   24a, 25 25 CH 2.68 (m)  41.6 24a,b, 46 24b, 46 26 C═O N/An.d. (>210) n.d. N/A 27 CH—OCH₃ 3.83 (m)  85.0 28, 51 28 28 CH—OH 4.23(d, 4.4 Hz)  76.7 27, 30, 47 27 29 —C═ N/A 136.3 28, 31, 47 N/A 30 CH═C5.43 (d, 9.8 Hz) 126.3 28, 31, 47, 48 31, 47 31 CH 3.31 (m)  46.6 30, 4830, 48 32 C═O N/A 208.3 30, 31, 33a,b, 48 N/A 33 CH₂ a: 2.69 (m)  40.5n.d. 33b, 34 b: 2.57 (m)   33a, 34 34 CH—OCO 5.15 (dd, 10.8, 5.5 Hz) 75.6 33a,b, 49 33a,b, 35 35 CH 1.92 (m)  33.3 33a,b, 49 34, 36a,b, 4936 CH₂ a: 1.17 (m)  38.4 34, 38b, 49 36b, 35 b: 1.09 (m)  36a, 35 37 CH1.33 (m)  33.0 36a,b, 38a,b, 42a,b 38b, 42a,b 38 CH₂ a: 2.02 (m)  36.236a,b, 42a 38b, 39 b: 0.70 (m)   38a, 37, 39 39 CH—OCH₃ 3.04 (m)  83.038a,b, 40, 41b, 52 38a,b, 40 40 CH—O— 3.11 (m)  83.0 38a,b, 39, 52 39,41a,b 41 CH₂ a: 2.01 (m)  30.0 42b. 41b, 40, 42b b: 1.22 (m) 41a, 40,42b 42 CH₂ a: 1.67 (m)  31.6 38a,b 42b, 37 b: 0.88 (m) 42a, 37, 41a,b 4311-CH₃ 0.95 (3H, d, 6.6 Hz)  16.1 11, 12 11 44 17-CH₃ 1.66 (3H, s)  10.216, 18 18 45 23-CH₃ 1.05 (3H, d, 6.6 Hz)  21.4 22, 24a,b 23 46 25-CH₃0.98 (3H, d, 6.3 Hz)  13.5 24a,b, 25 25 47 29-CH₃ 1.77 (3H, s)  13.5 28,30 30 48 31-CH₃ 1.07 (3H, d, 6.8 Hz)  15.9 30, 31 31 49 35-CH₃ 0.89 (3H,d, 6.8 Hz)  15.7 36a 35 50 16-OCH₃ 3.14 (3H, s)  55.9 16 n.d. 51 27-OCH₃3.34 (3H, s)  59.0 27 n.d. 52 39-OCH₃ 3.42 (3H, s)  57.7 39 n.d. 5340-OCH₂ 3.73 (2H, m)  69.1 40, 54 54 54 —CH—O— 3.66 (2H, m)  70.1 53, 5553 55 —OCH₂triazole 4.68 (2H, s)  64.5 54 57 56 —C═ N/A 145.0 55, 57 N/A57 ═CH 7.77 (s) 123.9 55, 95 55 58 PP—C N/A 144.6 65, 67, 68 N/A 59 PP—CN/A  98.8 61 N/A 60 PP—C—NH₂ N/A 157.9 61 N/A 61 PP—CH 8.33 (s) 155.5n.d. n.d. 62 PP—C N/A 154.2 61, 72 N/A 63 BO—C—NH₂ N/A 165.8 n.d. N/A 64BO—C N/A 144.6 65, 68 N/A 65 BO—CH 7.61 (s) 116.1 67, 68 67 66 BO—C N/A129.2 68 N/A 67 BO—CH 7.37 (d, 8.4 Hz) 121.6 65 65, 68 68 BO—CH 7.39 (d,8.4 Hz) 109.7 65, 67 67 69 BO—C N/A 149.1 65, 67, 68 N/A 72 N—CH₂ 4.45(2H, t, 7.0 Hz)  46.6 73, 74 73 73 CH₂ 2.01 (2H, m)  27.3 72, 74, 75 72,74 74 CH₂ 1.58 (2H, m)  26.5 72, 73, 75 73, 75 75 CH₂—NHCO 3.31 (2H, m) 38.9 73, 74, 76 74 76 NH 6.86 (t, 5.5 Hz) N/A N/A n.d. 77 CO N/A 171.675, 76, 78, 79 N/A 78 CH₂ 2.45 (2H, t, 6.0 Hz)  37.0 79 79 79 CH₂ 3.70(2H, t, 6.0 Hz)  67.4 78 78 80-85 O—(CH₂CH₂O)₇ 3.54-3.64 (12H, m) 70.2-70.6 multi multi 86 OCH₂ 3.85 (2H, t, 5.0 Hz)  69.5 95 95 87CH₂-triazole 4.52 (2H, t, 5.1 Hz)  50.2 94 94 PPstands forpyrazolo[3,4-d]pyrimidine and BO stands for benzo[d]oxazole OHprotonsand NHx protons were not identified.

F. Example 6

Comparison Between Three Classes of mTOR Inhibitors (Rapamycin-Class I,MLN0128—Class II, and Rapa-Link-Class III). Human colorectal carcinomacell line HCT-15, human hepatocellular carcinoma cell line SNU-449,human renal cancer cell line 786-0, L⁶ myoblasts and 3T3-L¹ cells werepurchased from American Type Culture Collection (ATCC) (Manassas, Va.USA). The cells were grown in appropriate medium (vender recommended)supplemented with 10% heat-inactivated fetal bovine serum (FBS), intissue culture dishes placed in a humidified incubator maintained at 37°C. in an atmosphere of 5% CO₂ and 95% air.

Cell viability assay. Cells were seeded in a 96-multiwell plate at3000-4000 cells per well in medium containing FBS and cells wereincubated at 37° C. overnight. After 18-20 h, compounds in 10×DMSOsolution (n=3) were added to the cells and were incubated for additional3 days in a humidified incubator in an atmosphere of 5% CO₂ and 95% air.After treatment of Cell Titer-Glo® luminescent cell viability assayreagent (Promega Corporation, Madison, Wis. USA), the luminescence valuewas recorded using SpectraMax M5 Multi-Mode Microplate Readers(Molecular Devices, LLC, Sunnyvale, Calif. USA). Concentration responsecurves were generated on GraphPad Prism (GraphPad Software, La Jolla,Calif. USA) by calculating the decrease in luminescence values incompound-treated samples relative to the DMSO controls.

Anti-proliferative effects of compounds were evaluated in humancolorectal cancer HCT-15 cells (mutation: KRAS, PIK3CA), humanhepatocellular carcinoma SNU-449 (mutation: TP53, CDKN2A), SNU-398(mutation: CTNNB1), SNU-182 (mutation: TP53) and renal adenocarcinoma786-0 (mutation: VHL, PTEN, TP53, CDKN2A) in 72 h after compoundtreatment. Rapa-Link inhibitors M-1071 and M-1111 showed potent growthinhibitory activity (Table 9). Stronger anti-proliferative activities[EC₅₀ (nM): M-1071; ++++ (SNU-398), ++++ (SNU-449), ++++ (786-0), ++++(HCT-15), ++++ (SNU-182), and M-1111; ++++ (SNU-398), ++++ (SNU-449),+++(786-0), +++(HCT-15), ++++ (SNU-182)] were observed compared toMLN0128 [EC₅₀ (nM): +++(SNU-398), +++(SNU-449), ++(786-0), ++(HCT-15),++(SNU-182)]. In contrast, a shorter version of RapaLINK M-1115 showsless anti-proliferative activity [EC₅₀ (nM): +++(SNU-182), +++(SNU-398),+(HCT-15), +(SNU-449 and 786-0)].

TABLE 9 EC₅₀ (nM) values of Rapa-LINK inhibitors (vs. asTORi) SNU-398SNU-449 786-O HCT-15 SNU-182 M-1071 ++++ ++++ ++++ ++++ ++++ M-1111 ++++++++ +++ +++ ++++ M-1115 +++ + + + +++ MLN0128 +++ +++ ++ ++ ++ (++++ =<10 nM, 10 nM < +++ < 50 nM, 50 nM < ++ < 100 nM, 100 nM < +)

Table 10 represents % inhibition at 10 μM of Rapa-LINK inhibitors (vs.Rapamycin). Rapa-LINK inhibitors showed more potent inhibition incellular proliferation compared to Rapamycin

TABLE 10 % inhibition at 10 μM of Rapa-LINK inhibitors (vs. Rapamycin)SNU-398 SNU-449 786-O HCT-15 SNU-182 M-1071 +++ ++ ++ +++ ++ M-1111 +++++ +++ +++ ++ M-3059 +++ + n.d. n.d. + Rapamycin ++ + + ++ + (n.d.: notdetermined, + = ≤25%, 25% < ++ ≤ 50%, 50% < +++ ≤ 100%)

Since the Rapa-Link compound contains two classes of mTOR inhibitor, wewondered if the superior efficacy of M-1071 could be attributed to a“linker independent” synergy of these two agents, as reported byothers²¹. We compared the effect of M-1071 with a combination ofrapamycin and MLN0128 (FIG. 5B). Even when both Rapamycin and MLN0128were combined, their efficacy was inferior to M-1071. These resultssuggest that the enhanced anti-proliferative effect of the Class IIImTOR inhibitor, M-1071 is derived from its particular property of beinga single “linked” molecule, and not simply a mixture of an asTORi withRapamycin.

G. Example 7

Cellular Signaling Effects of Class I-II-III mTOR Inhibitors. Cells wereseeded in 60 mm cell culture dishes and incubated 1-2 days until 70-90%confluency. Cells were treated with compound solution in DMSO (1000×)and incubated at 37° C. in a 5% CO₂ humidified incubator for a givenlength of time. Whole cell lysates were prepared using RIPA buffer(R3792) (TEKnova, Hollister, Calif. USA) with a phosphatase inhibitorcocktail tablet PhosStop and a protease inhibitor cocktail tabletcOmplete Mini (Roche Diagnostics GmbH, Mannheim, Germany). Cell lysates(based on a certain amount of protein determined by Pierce BCA ProteinAssay Kit (PI-23225) (Thermo Fisher Scientific Inc., Waltham, Mass.USA)) were electrophoresed using a Criterion Tris-HCl gel 4-20% (Bio-RadLaboratories, Hercules, Calif. USA) and transferred to a nitrocellulosemembrane (162-0115) (Bio-Rad Laboratories, Hercules, Calif. USA). Afterincubation for more than 1 h with a blocking buffer at room temperature,membranes were labeled with primary antibodies by overnight incubationat 4° C., followed by 1 hour incubation with horseradishperoxidase-conjugated (HRP-conjugated) secondary antibodies at roomtemperature. The following antibodies were used for immunoblot:phospho-Akt (S473) (#9271), phospho-Akt (T308) (#2965), total-Akt(#9272), phospho-S6 (Ser240/Ser244) (#2215L), S6 ribosomal protein(#2217), phospho-4E-BP1 (T37/T46) (#2855), total 4E-BP1 (#9644) (CellSignaling Technology, Inc., Danvers, Mass. USA), FKBP12 (sc-28814) mouseβ-actin (sc-8432) (Santa Cruz Biotechnology, Inc., Dallas, Tex. USA),anti-rabbit IgG conjugated with horseradish peroxidase (HRP) (#7074),and anti-mouse IgG conjugated with HRP (#7076) (Cell SignalingTechnology, Inc., Danvers, Mass. USA). Nitrocellulose membranes wereexposed with SuperSignal® West Pico Chemiluminescent Substrate or FemtoMaximum Sensitivity Substrate (Thermo Fisher Scientific Inc., Waltham,Mass. USA) and signals were recorded on a CL-Xposure film (Thermo FisherScientific Inc., Waltham, Mass. USA).

Downstream signaling of mTOR was tested using an immunoblotting methodat 3 h after compound treatment. Although the active site inhibitorMLN0128 shows pan-mTORC1/2 downstream inhibition (pS6, p4E-BP1 and pAktS473) in both HCT-15 and SNU-449 cells (FIG. 7, and FIG. 8A), hybridinhibitors M-1071 and M-1111 showed stronger inhibition of mTORC1signaling (pS6 and p4E-BP1) compared to mTORC2 downstream Akt S473phosphorylation. Interestingly, M-1071 and M-1111 showed completep4E-BP1 inhibition at drug concentrations in which pAkt S473 is notinhibited. These selective modulations of mTORC1 vs mTORC2 have not beenachieved by asTORi. On the other hand, M-1115 with a short cross-linkershowed weaker p4E-BP1 inhibition. These structure activity relationshipsexplain that potent anti-proliferative activity is derived from mTORC1complete inhibition (p4E-BP1 and pS6) and that TORC2 inhibition (pAkt)may not enhance anti-proliferative activity in these cell lines.

Although short-term rapamycin treatment shows selective inhibition ofmTORC1, it was reported that prolonged treatment of rapamycin alsoinhibits mTORC2 in various cells²². We examined time-course effects of aRapa-Link inhibitor on mTORC1 and mTORC2 signaling in SNU-449 (FIG. 8B).Treatment of MLN0128 blocked phosphorylation of pAkt S473 continuouslyduring 0.33-24 h. Treatment of M-1071 or rapamycin treatment underwenttransient feedback activation on Akt S473 at 1 and 3 h, and then aslight inhibition was observed at 24 h. The feedback activationfollowing Rapamycin treatment has been reported by Rosen andcolleauges²³. pS6 was consistently inhibited by all inhibitors after 3 hto 24 h. Interestingly, response of p4E-BP1 inhibition was varied amonginhibitors. Treatment of MLN0128 completely inhibited p4E-BP1 in earlyonset (0.33-1 h) and then partial phosphorylation of 4E-BP1 was observedafter 3 h to 24 h. This is likely mediated by feedback reactivation ofthe Akt-mTOR pathway as reported by Rosen and colleagues²⁴. In contrast,M-1071 treatment provided continuous complete inhibition of TORC1outputs within 3-24 h. Treatment of rapamycin showed moderate inhibitoryactivity against p4E-BP and the potency slightly increased intime-dependent manner. We conclude that M-1071's continuous and strongcellular activities (such as inhibition of p4E-BP1) might be derivedfrom the ability to bind to both the FRB domain and the ATP site ofmTOR.

H. Example 8

Pharmacodynamic studies of M1071 in human renal cancer 786-0 xenografttumor in mice. M-1071 was intraperitoneally administered to tumortransplanted mice by using Cremophor EL-ethanol [2/1 w/w], and dilutingthis 1:5 with 5% w/v glucose in water as a vehicle. Tumor samples werecollected at 3 h after drug administration. For the MWF group, M-1071was administered once daily every other day. At 4 h after the lastadministration, tumor samples were collected. After the freezing tumorsamples, they were homogenized and treated with RIPA buffer containingphosphatase inhibitor and protease inhibitor. The following westernblotting analysis were conducted in a similar way to abovementionedmethod.

In the drug treated groups, dose dependent inhibition againstphospho-4E-BP1 was observed (FIG. 9). Phosphorylation of S6 was alsoinhibited by the treatment of M-1071. On the other hand, inhibition ofphospho-S473 of Akt was slight even at highest dosing of 5 mg/kg whichdemonstrated the complete inhibition of pS6 and p4EBP-1.

I. Example 9

Effect on blood glucose level. M-1071, Rapamycin and MLN0128 wereintraperitoneally administered to mice (n=3) by using CremophorEL-ethanol [2/1 w/w], and diluting this 1:5 with 5% w/v glucose in wateras a vehicle. Blood glucose levels (mg/dL) were monitored.

It was reported that Akt inhibition by the treatment with Akt inhibitorresults in a transient increase in blood glucose in mice²⁵. BecausemTORC2 plays a central role in full activation of Akt viaphosphorylation of S473 on Akt, monitoring the blood glucose level isthought to be a good readout for mTORC2 inhibition by an mTOR inhibitor.Compared with the vehicle treatment group which showed a slight increasein blood glucose at 15 min, perhaps due to the injection of glucosecontaining vehicle, MLN0128 treatment groups (1, 3, 5 mg/kg) showed atransient increase in blood glucose level at 30 min (FIG. 10). Incontrast, the M-1071 treatment group (5 mg/kg) showed a significantlysmaller increase in blood glucose level at 30 min. Furthermore, M-1071(1, 3 mg/kg) and Rapamycin treatment groups showed no increase in bloodglucose levels.

In combination with the aforementioned in vivo pharmacodynamic studyresults, these results indicate that M-1071 demonstrates mTORC1selectivity vs. mTORC2 in a mouse model at efficacious doses of mTORC1inhibition.

J. Example 10

Drug Washout Experiment. SNU-449 cells were treated with 30 nM ofcompounds for 3 h. The medium was aspirated out and cells were washedwith fresh 10% FBS in RPMI1640 medium. Then, cells were incubated withfresh 10% FBS in RPMI1640 medium at 37° C. for described time period.

In contrast to MLN0128 washout in which inhibitory effects rapidlydisappeared within 1 h, M-1071 treatment showed sustained inhibitoryeffects in both p4E-BP1 (at least 2 h) and pS6 (at least 4 h). Based onthese results, we assumed that the effects with MLN0128 areconcentration-dependent because asTORi competes with high concentrationof cellular ATP. In contrast, Rapamycin effects tend to be maintainedlonger after washout compared to asTORi because Rapamycin is not bindingto the catalytic site. By utilizing the allosteric characteristics ofRapamycin, the ATP site inhibitor portion of the Rapa-link compound ismost likely to be able to stay in the ATP site and overcomes thecompetition with high concentration of cellular ATP.

References 1. Kim, D.-H. et al. Cell 110, 163-175 (2002)₂. Hara, K. etal. Cell 110, 177-189 (2002). 3. Sarbassov, D. D. et al. Curr Biol 14,1296-1302 (2004). 4. Jacinto, E. et al. Nat Cell Biol 6, 1122-1128(2004). 5. Ruggero, D. et al. Nature Medicine 10, 484-486 (2004). 6.Feldman, M. E. et al. PLoS Biol 7, e38 (2009). 7. Neasta, J., et al.Journal of Neurochemistry (2014). doi:10.1111/jnc.127258. Thoreen, C. C.et al. J Biol Chem 284, 8023-8032 (2009). 9. Liu, Y., et al. Science(2010). 10. Hsieh, A. C. et al. Cancer Cell 17, 249-261 (2010). 11.Hsieh, A. C. et al. Nature 485, 55-61 (2012). 12. Infante, J. R. et al.Abstract C252: A phase 1, dose-escalation study of MLN0128, aninvestigational oral mammalian target of rapamycin complex 1/2(mTORC1/2) catalytic inhibitor, in patients (pts) with advancednon-hematologic malignancies. Mol. Cancer Ther., 12; C252, (2013). 13.Shih, K. C. et al. J Clin Oncol 30, (2012). 14. Naing, A. et al. Br JCancer 107, 1093-1099 (2012). 15. O'Donnell, A. et al. J Clin Oncol 26,1588-1595 (2008). 16. Wood, E. R. et al. Cancer Res 64, 6652-6659(2004). 17. Yang, H. et al. Nature 1-8 (2013).doi:10.1038/nature1212218. Choi, J., et al. Science 273, 239-242 (1996).19. Ayral-Kaloustian, S. et al. J Med Chem 53, 452-459 (2010). 20.Banerjee, S. S., et al. J Drug Deliv 2012, 103973 (2012). 21. Xu, C.-X.et al. PLoS ONE 6, e20899 (2011). 22. Hsu, P. P., et al. Mol Cell(2006). 23. O'Reilly, K. E. et al. Cancer Res 66, 1500-1508 (2006). 24.Rodrik-Outmezguine, V. S. et al. Cancer Discovery 1, 248-259 (2011). 25.Rhodes, N. et al. Cancer Res 68, 2366-2374 (2008).

K. Example 11

Additional Rapa-LINK compounds. Two additional Rapa-LINK compounds,E1010 and E1035, were synthesized to explore the effects of a weakerbinder to the ATP site of mTOR.

The first Rapa-LINK inhibitor, M1071, combined the allosteric inhibitor,rapamycin, with the ASi, MLN-0128. E1035 and E1010 combined rapamycinwith the known ASi, PP242, and a PP242 derivative, MeO-PP242,respectively (FIG. 12).

The potency of the ASi mTOR inhibition in the Rapa-LINK compounds orderfrom strongest to weakest as follows: MLN0128 (<1 nM), PP242 (IC50=8 nMFeldman, M. E., et al. (2009). PLoS Biology, 7(2), e38), MeO-PP242 (>10μM). The strongest ASi, MLN0128, in M1071 leads to a potent mTORC1inhibition (10-25 nM) (FIG. 13A). In this concentration range, M1071also inhibits mTORC2. However, E1035, which uses PP242 as the ASi, showsa similar mTORC1 inhibition concentration range (10-25 nM) but requiresa higher concentration range for mTORC2 inhibition (partial inhibitionat 50 nM) (FIG. 13A). Lastly, the weakest ASi, MeO-PP242, in E1010 leadsto inhibition of pS6 (S240/244) but little or no inhibition of P-4EBP1(FIG. 13B). This pattern of inhibition is similar to rapamycin inducedphosphorylation changes with only phosphorylation of S6 after E1010treatment (FIG. 8A and FIG. 13B). Thus, the specificity of the Rapa-LINKcompounds shifts more towards mTORC1 as the ASi potency decreases.

We assessed the effects of mTORC1 inhibition by Rapa-LINK compounds oncell proliferation. E1010 and rapamycin had similar effects on cellproliferation in 786-0 cells (FIG. 14A). This agrees with the E1010rapamycin-like mTOR inhibition profile seen in FIGS. 13A-13B. Inmeasuring cell proliferation effects of the more potent Rapa-Linkcompounds, E1035 and M1071 both have potent effects on cellproliferation (FIG. 13B). The cell proliferation effects of E1035 andM1071 are quite similar, even though the former exhibits a larger windowbetween TORC1 and TORC2 inhibition. This data supports the view thatanti-proliferative effects rely on TORC1 rather than TORC2 inhibition,as discussed above.

Methods.

Chemical Synthesis. All compounds were synthesized from commerciallyavailable starting materials and purified by RP-HPLC.

Cell Culture and Western Blot Analysis. Cells were grown in 6-wellplates and treated with inhibitor at the indicated concentrations orwith vehicle (0.1% DMSO). Treated cells were lysed, and lysates wereresolved by SDS-PAGE, transferred to nitrocellulose and blotted. Allantibodies were purchased from Cell Signaling Technology.

Cell proliferation assays. Cells grown in 96-well plates were treatedwith inhibitor in triplicate or vehicle (0.1% DMSO). After 72 h, cellviability was assessed with the CELLTITER-GLO® Luminescent CellViability Assay (Promega). Cell proliferation curves were generatedusing Prism.

Supplementary Information.

Abbreviations. AcOH: acetic acid, DCM: dichloromethane, DME:1,2-dimethoxyethane, DMF: N,N-dimethylformamide, DMSO:dimethylsulfoxide, dPEG: discrete poly-(ethylene glycol), ESI:electrospray ionization, EtOAc: ethyl acetate, HPLC: high performanceliquid chromatography, HR-MS: high resolution mass spectroscopy, LC-MS:liquid chromatography-mass spectrometry, LTQ-FT: linear trapquadrupole-Fourier transform, MeOH: methanol, NHS: N-hydroxysuccinimide,NMR: nuclear magnetic resonance, RP-HPLC: reverse phase-high performanceliquid chromatography, THF: tetrahydrofuran, TLC: thin layerchromatography, TMS: tetramethylsilane.

Materials and Methods. Starting materials, reagents, and solvents forreactions were of reagent grade and were used as purchased.Chromatographic purification was carried out using silica gel (Merck,70-230 mesh). RP-HPLC was carried out on a Waters Binary Gradient Module2545 system equipped with an Agilent Zorbax 300-SB C18 column (5 μm,4.6×250 mm) for analytical mode or a Waters XBridge Prep C18 column (5μm, 30×250 mm) for preparative mode. The column was eluted withCH3CN/water/0.1% formic acid (gradient mode), which was monitored byWaters Photodiode Array Detector 2998 (UV at λ=254 nm). Yields were notoptimized.

¹H NMR spectra for intermediates were recorded on a Varian INOVA™ (400MHz) spectrometer. ¹H NMR spectra, ¹H-¹H COSY, HSQC, and HMBC spectrafor final compounds were recorded on a Bruker AVANCE™ (800 MHz)spectrometer. ¹³C NMR spectra were recorded on a Bruker AVANCE™ (500MHz) spectrometer (500 MHz for ¹H, 126 MHz for ¹³C). ¹H chemical shiftsare reported in δ (ppm) as s (singlet), d (doublet), t (triplet), q(quartet), dd (double doublet), m (multiplet) or br s (broad singlet)and are referenced to TMS (trimethylsilane) as an internal standard.LC-MS (ESI-MS) spectra were recorded with a Waters 2695 separationsmodule using a Waters ACQUITY UPLC® BEH C₁₈ 1.7 μm column and were usedto confirm ≥95% purity of each compound. Mobile phase A was 0.1% formicacid in ultrapure water. Mobile phase B was 0.1% formic acid inacetonitrile. (flow rate: 0.6 mL/min). HR-MS analysis was conducted byQB3/Chemistry Mass Spectrometry Facility in UC Berkeley. Samples wereanalyzed by electrospray ionization with a mass measuring accuracy of 5ppm using the LTQ-FT instrument.

Experimental Procedures

Preparation of Compound (E1010)

Preparation of tert-butyl(4-(4-amino-3-(5-methoxy-1H-indol-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)butyl)carbamate2. To a bi-phasic suspension of tert-butyl(4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)butyl)carbamate (1)(260 mg, 0.604 mmol), (2) and 1-BOC-5-methoxyindole-2-boronic acid (444mg, 1.52 mmol), and saturated aqueous Na₂CO₃ solution (2 mL) in DME (10mL) was added tetrakis(triphenylphosphine) palladium(0) (69.3 mg, 60μmol) at room temperature under argon atmosphere. The mixture wasstirred at 85° C. for 20 h. It was then cooled and partitioned betweenEtOAc (50 mL) and water (50 mL). The aqueous layer was separated andextracted with EtOAc (50 mL). The organic layers were combined, washedwith brine (50 mL) and dried over anhydrous MgSO₄. The insoluble wasfiltered off and the filtrate was concentrated in vacuo. The crudematerial was purified by silica gel column chromatography (silica gel:125 g, solvent: 100% EtOAc followed by 30% MeOH in EtOAc). ¹H NMR (400MHz, CDCl₃) δ 9.84 (1H, br s), 8.36 (1H, s), 7.36 (1H, d, J=8.8 Hz),7.12 (1H, d, J=2.2 Hz), 6.92 (1H, dd, J=8.8, 2.5 Hz), 6.80 (1H, s), 6.43(2H, t, br s), 4.82 (1H, br s), 4.43 (2H, t), 3.86 (3H, s), 1.44 (9H,s), 6H protons were not identified. LC-MS (ESI) m/z=452.79 (M+H)⁺.

Preparation ofN-(4-(4-amino-3-(5-methoxy-1H-indol-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)butyl)-1-azido-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-amide3. To an aliquot of TFA (2 mL) was added tert-butyl(4-(4-amino-3-(5-methoxy-1H-indol-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)butyl)carbamate(2) (205 mg, 0.454 mmol) at 4° C. The mixture was stirred at ambienttemperature for 30 min. It was then evaporated in vacuo. Drying thesolid gave the salt of Boc-cleaved compound. The obtained material wasdissolved into DMF (4 mL). To the mixture was added triethylamine (144μL, 1.03 mmol) followed by a solution of azide-dPEG8-NHS ester (175 mg,0.310 mmol) in DMF (1 mL) under argon atmosphere. The mixture wasstirred at room temperature for 1 h. It was then evaporated in vacuo.The residue was partitioned between 10% THF in EtOAc (100 mL) and brine(70 mL). The aqueous layer was separated and extracted with EtOAc (70mL). The organic layers were combined and dried over anhydrous MgSO₄.The insoluble was filtered off and the filtrate was evaporated in vacuo.The resulting crude material was purified by silica gel columnchromatography (silica gel: 25 g, 0-15% MeOH in DCM). Desired fractionswere combined and evaporated in vacuo to give the titled compound (123mg, 59.3% in 2 steps) as a wax. ¹H NMR (400 MHz, CDCl₃) δ 9.94 (1H, brs), 8.37 (1H, s), 7.40 (1H, d, J=8.9 Hz), 7.11 (1H, d, J=2.4 Hz), 6.92(1H, dd, J=8.8, 2.4 Hz), 6.79 (1H, s), 6.06 (2H, br s), 4.48 (2H, m),3.88 (3H, s), 3.70 (2H, m), 3.61 (30H, m), 3.37 (2H, m), 3.32 (2H, m),2.44 (2H, m), 2.01 (4H, m). LC-MS (ESI) m/z=802.08 (M+H)⁺.

Preparation of E1010 4. To a solution of 3 (32.0 mg, 43.0 μmol) in MeOH(4 mL) was added 40-O-(2-(prop-2-yn-1-yloxy)ethyl)-rapamycin (32.5 mg,32.6 μmol). To the mixture were added 1 M aqueous CuSO₄ solution (100μL, 100 μmol) and 1 M aqueous ascorbic acid solution (50.0 μL, 50.0μmol). The mixture was stirred at room temperature for 1.5 h. It wasthen concentrated in vacuo. The obtained material was triturated with10% THF in EtOAc (10 mL) for 10 min. After removing the insolublematerial by filtration through Celite filter-aid, the solution wasevaporated in vacuo. The resulting crude material was purified bypreparative RP-HPLC (40-85% CH₃CN in water containing 0.1% formic acid).The desired fractions were combined and lyophilized to give a formicacid salt of the titled compound (2.6 mg, 4%) as a colorless amorphouspowder. LC-MS (ESI−) m/z=1796.51 (M−H)⁻. HR-MS (ESI−) Calcd forC93H141O24N11 (M−Na)+ 1819.0043, Found 1819.0034 (Δ −0.50 ppm).

TABLE 11 NMR results for E-1010. E-1010

Atom Atom Type δ ¹H Major (3:1) δ ¹³C Major (3:1) HMBC C to H ¹H—¹H COSY 1 C═O N/A 169.2  2 N/A  2 CH 5.28 (d, 5.7 Hz)  51.3  3a,b, 6a  3b  3CH₂ a: 2.33 (s)  27.1  2, 5a  3b, 4b   b: 1.75 (m)      3a, 2  4 CH₂ a:1.78 (m)  20.7  2, 6a,b  4b, 5a,b   b: 1.47 (m)      4a, 3a, 5a,b  5 CH₂a: 1.74 (m)  25.3  3a, 4b  5b, 4a,b   b: 1.47 (m)      5a, 4a,b, 6b  6CH₂ a: 3.56 (m)  44.2  2, 4b, 5b  6b   b: 3.43 (m)    6a, 5b  8 C═O N/A166.7  2, 6a N/A  9 C═O N/A 196.2 n.d. N/A 10 O—C—OH N/A  98.5 12, 43N/A 11 CH 2.00 (m)  33.8 12, 43 12, 43 12 CH₂ 1.60 (2H, m)  27.2 43 11,13a,b 13 CH₂ a: 1.63 (m)  31.2 12, 15a 13b, 12 b: 1.31 (m)   13a, 12, 1414 CH—OC 3.88 (m)  67.3 12, 15a 13b, 15a,b 15 CH₂ a: 1.85 (m)  38.9 1615b, 14, 16 b: 1.49 (m)   15a, 14, 16 16 CH—OCH₃ 3.65 (m)  84.3 15a, 18,44, 50 15a,b 17 —C═ N/A 135.7 15a, 44 N/A 18 CH═C 5.97 (d, 10.9 Hz)129.4 44 19 19 CH═C 6.38 (dd, 14.5, 11.6 Hz) 126.6 20, 21 18, 20 20 CH═C6.31 (dd, 14.8, 10.4 Hz) 133.5 18, 19, 21, 22 19, 21 21 CH═C 6.14 (dd,14.8, 10.4 Hz) 130.2 19 20, 22 22 CH═C 5.55 (dd, 15.1, 8.9 Hz) 140.0 20,24a,b, 45 21, 23 23 CH 2.32 (m)  35.0 21, 22, 24a,b, 25, 45 22, 24a, 4524 CH₂ a: 1.47 (m)  40.3 22, 25, 45, 46 24b, 23 b: 1.21 (m)   24a, 25 25CH 2.70 (m)  40.8 24a,b, 46 24b, 46 26 C═O N/A n.d. (>210) n.d. N/A 27CH—OCH₃ 3.78 (m)  84.9 28, 51 28 28 CH—OH 4.19 (d, 5.24 Hz)  77.1 27,30, 47 27 29 —C═ N/A 136.0 28, 31, 47 N/A 30 CH═C 5.42 (d, 9.9 Hz) 126.628, 31, 47, 48 31 31 CH 3.29 (d, 10.4 Hz)  46.6 30, 48 30, 48 32 C═O N/A208.3 30, 31, 33a,b, 48 N/A 33 CH₂ a: 2.70 (m)  40.7 n.d. 33b, 34 b:2.58 (dd, 15.7, 8.6 Hz)   33a, 34 34 CH—OCO 5.16 (dd, 10.7, 5.9 Hz) 75.8 33a,b, 49 33a,b, 35 35 CH 1.93 (m)  33.2 33a,b, 49 34, 36a,b, 4936 CH₂ a: 1.17 (m)  38.3 38b, 49 36b, 35, 37 b: 1.09 (m)   36a, 35, 3737 CH 1.33 (m)  33.1 36a,b, 38b, 42b 36a,b, 38b, 42a,b 38 CH₂ a: 2.02(m)  36.3 36a,b, 42a 38b, 39 b: 0.70 (m)   38a, 37, 39 39 CH—OCH₃ 3.04(m)  83.2 38a,b, 40, 52 38a,b, 40 40 CH—O— 3.10 (m)  83.2 38a,b, 39, 52,53 39, 41a,b 41 CH₂ a: 2.01 (m)  30.1 n.d. 41b, 40, 42b b: 1.24 (m)  41a, 40, 42b 42 CH₂ a: 1.66 (m)  31.8 36b, 38a 42b, 37 b: 0.90 (m)  42a, 37, 41a,b 43 11-CH₃ 0.95 (3H, d, 6.7 Hz)  16.2 n.d. 11 44 17-CH₃1.65 (3H, s)  10.2 16, 18 n.d. 45 23-CH₃ 1.05 (3H, d, 6.4 Hz)  21.5 22,24a,b 23 46 25-CH₃ 0.99 (3H, d, 6.4 Hz)  13.7 24a,b, 25 25 47 29-CH₃1.75 (3H, s)  13.2 28, 30 n.d. 48 31-CH₃ 1.09 (3H, d, 6.9 Hz)  16.0 30,31 31 49 35-CH₃ 0.90 (3H, d, 6.4 Hz)  15.9 36a,b 35 50 16-OCH₃ 3.14 (3H,s)  55.9 16 n.d. 51 27-OCH₃ 3.33 (3H, s)  59.3 27 n.d. 52 39-OCH₃ 3.43(3H, s)  57.9 39 n.d. 53 40-OCH₂ 3.70 (2H, m)  69.3 40, 54 54 54 —CH₂—O—3.66 (2H, m)  70.1 53, 55 53 55 —OCH₂triazole 4.68 (2H, d, 4.9 Hz)  64.654 n.d. 56 —C═ N/A 145.0 55, 57 N/A 57 ═CH 7.71 (s) 123.8 55, 97 n.d. 58PP—C N/A 144.5 65 N/A 59 PP—C N/A  98.5 61 N/A 60 PP—C—NH₂ N/A 157.5n.d. N/A 61 PP—CH 8.36 (s) 156.0 n.d. n.d. 62 PP—C N/A 154.1 61, 74 N/A63 Ind-NH 9.99 (s, br) N/A N/A n.d. 64 Ind-C N/A 131.1 63, 65 N/A 65Ind-CH 6.80 (s) 101.7 n.d. n. d. 66 Ind-C N/A 101.7 65, 67, 70 N/A 67Ind-CH 7.11 (d, 1.3 Hz) 102.0 n. d. 69 68 Ind-C N/A 113.7 67, 69 N/A 69Ind-CH 6.92 (dd, 2.1, 9.1 Hz) 113.7 n. d. 67, 70 70 Ind-CH 7.40 (d, 8.0Hz) 112.5 n. d. 69 71 Ind-C N/A 130.0 63, 70 N/A 73 Ind-O—CH₃ 3.87 (3H,s)  55.9 n.d. n. d 74 N—CH 4.48 (2H, t, 6.7 Hz)  46.6 75, 76 75 75 CH₂2.01 (2H, m)  26.8 74, 75, 76 74, 75 76 CH₂ 1.56 (2H, m)  26.4 74, 75,77 75, 77 77 CH₂—NHCO 3.32 (2H, m)  38.8 75, 76 76 78 NH 6.83 (s) N/AN/A n.d. 79 CO N/A 171.6 77, 80, 81 N/A 80 CH₂ 2.45 (2H, t, 5.3 Hz) 37.1 81 81 81 CH₂ 3.74 (2H, t, 4.4 Hz)  67.4 80 80 82-95 O—(CH₂CH₂O)₇3.56-3.60 (28H, m)  70.4-70.5 multi multi 96 OCH₂ 3.84 (2H, t, 5.3 Hz) 69.5 97 97 97 CH₂-triazole 4.51 (2H, t, 5.1 Hz)  50.2 96 96 PPstandsfor pyrazolo[3,4-d]pyrimidine and Ind stands for 1H-Indole OHproton wasobserved at 4.81 (1H, s) for 10-OH or 28-OH. Another OH proton was notidentified. NHx protons were observed at 6.08 (br) for PP NH₂.

Preparation of E1035 8

Preparation of tert-butyl2-(4-amino-1-(4-((tert-butoxycarbonyl)amino)butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-((tert-butyldimethylsilyl)oxy)-1H-indole-1-carboxylate6

To an aliquot of dioxane:H₂O (3:1) (1 mL) was added1-Boc-5-TBDMS-O-indole-2-boronic acid (5) (previously synthesized) (50mg, 0.12 mmol),(1-(tert-butoxycarbonyl)-5-((tert-butyldimethylsilyl)oxy)-1H-indol-2-yl)boronicacid (135 mg, 0.35 mmol), K₃PO₄ (34 mg, 0.35 mmol), SPhos (10.2 mg, 24.8μmol) and tris(dibenzylideneacetone)dipalladium(0) (12.2 mg, 13.3 μmol)at room temperature under argon atmosphere. The mixture was heated viamicrowave at 150° C. for 20 min. It was then cooled and partitionedbetween H₂O (5 mL) and DCM (5 mL). The aqueous layer was separated andextracted with DCM (5 mL×2). The organic layers were combined and driedover anhydrous MgSO₄. The insoluble was filtered off and the filtratewas concentrated in vacuo. The crude material was purified by silica gelcolumn chromatography (silica gel: 125 g, solvent: 100% DCM followed by0-10% MeOH in DCM). ¹H NMR (400 MHz, DMSO-d6) δ 11.43 (1H, br s), 8.42(1H, s), 8.27 (1H, s), 7.25 (1H, d, J=8.8 Hz), 7.12 (2H, br s), 6.92(1H, d, J=2.3 Hz), 6.69 (1H, dd, J=8.3, 2.3 Hz), 6.68 (1H, br s), 4.38(2H, t, J=6.4 Hz), 3.58 (2H, br s), 2.76 (2H, t, J=7.1 Hz), 1.92 (2H,m), 1.50 (2H, m). LC-MS (ESI) m/z=550.81 (M−H)⁻.

Preparation ofN-(4-(4-amino-3-(5-hydroxy-1H-indol-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)butyl)-1-azido-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-amide7. To an aliquot of TFA (4 mL) was addedtert-butyl-2-(4-amino-1-(4-((tert-butoxycarbonyl)amino)butyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-(tertbutyldimethylsilyl)oxy)-1H-indole-1-carboxylate(2) (60 mg, 0.092 mmol). The mixture was stirred at ambient temperaturefor 1 hr. It was then evaporated in vacuo. The resulting crude materialwas purified by preparative RP-HPLC (40-85% CH₃CN in water containing0.1% formic acid). The desired fractions were combined and lyophilizedto give a formic acid salt of the material as a colorless amorphouspowder. The obtained material (29 mg, 0.067 mmol) was dissolved in DMF(1 mL). To the mixture was added triethylamine (37.38 μL, 0.268 mmol)followed by a solution of azide-dPEG8-NHS ester (46 mg, 0.081 mmol) inDMF (0.5 mL) under argon atmosphere. The mixture was stirred at roomtemperature for 1 h. The resulting crude material was purified bypreparative RP-HPLC (40-85% CH₃CN in water containing 0.1% formic acid).Desired fractions were combined and evaporated in vacuo to give thetitled compound (40 mg, 75.9% in 2 steps) as an orange oil. ¹H NMR (400MHz, CDCl₃) δ 9.96 (1H, br s), 8.31 (1H, s), 7.24 (1H, d, J=8.5 Hz),7.02 (1H, d, J=1.9 Hz), 6.85 (1H, br s), 6.81 (1H, dd, J=8.1, 2.2 Hz),6.64 (1H, s), 6.28 (2H, br s), 4.39 (2H, t, J=6.85 Hz), 3.57 (32H, m),3.24 (2H, m), 3.22 (2H, m), 2.39 (2H, m), 1.93 (2H, m), 1.47 (2H, m), NHnot identified. LC-MS (ESI) m/z=788.03 (M+H)⁺.

Preparation of E1035 8. To a solution of 3 (25 mg, 32.6 μmol) in MeOH (2mL) was added 40-O-(2-(prop-2-yn-1-yloxy)ethyl)-rapamycin (24.8 mg, 24.9μmol). To the mixture were added 1 M aqueous CuSO₄ solution (37.7 μL,37.7 μmol) and 1 M aqueous ascorbic acid solution (42.7 μL, 42.7 μmol).The mixture was stirred at room temperature for 1.5 h. It was thenconcentrated in vacuo. The obtained material was triturated with 10% THFin EtOAc (10 mL) for 10 min. After removing the insoluble material byfiltration through Celite filter-aid, the solution was evaporated invacuo. The resulting crude material was purified by preparative RP-HPLC(40-85% CH₃CN in water containing 0.1% formic acid). The desiredfractions were combined and lyophilized to give a formic acid salt ofthe titled compound (1.9 mg, 4%) as a colorless amorphous powder. LC-MS(ESI−) m/z=1781.45 (M−H)⁻

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

What is claimed is:
 1. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein Y is O; R¹⁰⁰ is amonovalent active site mTOR inhibitor having the formula:

R²⁰ is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R²¹-substituted or unsubstituted alkyl, R²¹-substituted or unsubstitutedheteroalkyl, R²¹-substituted or unsubstituted cycloalkyl,R²¹-substituted or unsubstituted heterocycloalkyl, R²¹-substituted orunsubstituted aryl, or R²¹-substituted or unsubstituted heteroaryl; R²¹is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R²²-substituted or unsubstituted alkyl, R²²-substituted or unsubstitutedheteroalkyl, R²²-substituted or unsubstituted cycloalkyl,R²²-substituted or unsubstituted heterocycloalkyl, R²²-substituted orunsubstituted aryl, or R²²-substituted or unsubstituted heteroaryl; R²²is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, orunsubstituted heteroaryl; z20 is an integer from 0 to 5; L¹ isL²-L³-L⁴-L⁵; L² is connected directly to a monovalent rapamycin or amonovalent rapamycin 27 analog; L² is a R²⁶-substituted or unsubstituted2 to 8 membered heteroalkylene; L³ is a R²⁹-substituted or unsubstituted5 to 10 membered heteroarylene; L⁴ is a R³²-substituted or unsubstitutedC₁-C₂₀ alkylene or R³²-substituted or unsubstituted 2 to 20 memberedheteroalkylene; L⁵ is a R³⁵-substituted or unsubstituted C₁-C₂₀ alkyleneor R³⁵-substituted or unsubstituted 2 to 20 membered heteroalkylene; R²⁶is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R²⁷-substituted or unsubstituted alkyl, R²⁷-substituted or unsubstitutedheteroalkyl, R²⁷-substituted or unsubstituted cycloalkyl,R²⁷-substituted or unsubstituted heterocycloalkyl, R²⁷-substituted orunsubstituted aryl, or R²⁷-substituted or unsubstituted heteroaryl; R²⁷is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R²⁸-substituted or unsubstituted alkyl, R²⁸-substituted or unsubstitutedheteroalkyl, R²⁸-substituted or unsubstituted cycloalkyl,R²⁸-substituted or unsubstituted heterocycloalkyl, R²⁸-substituted orunsubstituted aryl, or R²⁸-substituted or unsubstituted heteroaryl; R²⁹is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R³⁰-substituted or unsubstituted alkyl, R³⁰-substituted or unsubstitutedheteroalkyl, R³⁰-substituted or unsubstituted cycloalkyl,R³⁰-substituted or unsubstituted heterocycloalkyl, R³⁰-substituted orunsubstituted aryl, or R³⁰-substituted or unsubstituted heteroaryl; R³⁰is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R³¹-substituted or unsubstituted alkyl, R³¹-substituted or unsubstitutedheteroalkyl, R³¹-substituted or unsubstituted cycloalkyl,R³¹-substituted or unsubstituted heterocycloalkyl, R³¹-substituted orunsubstituted aryl, or R³¹-substituted or unsubstituted heteroaryl; R³²is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R³³-substituted or unsubstituted alkyl, R³³-substituted or unsubstitutedheteroalkyl, R³³-substituted or unsubstituted cycloalkyl,R³³-substituted or unsubstituted heterocycloalkyl, R³³-substituted orunsubstituted aryl, or R³³-substituted or unsubstituted heteroaryl; R³³is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R³⁴-substituted or unsubstituted alkyl, R³⁴-substituted or unsubstitutedheteroalkyl, R³⁴-substituted or unsubstituted cycloalkyl,R³⁴-substituted or unsubstituted heterocycloalkyl, R³⁴-substituted orunsubstituted aryl, or R³⁴-substituted or unsubstituted heteroaryl; R³⁵is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R³⁶-substituted or unsubstituted alkyl, R³⁶-substituted or unsubstitutedheteroalkyl, R³⁶-substituted or unsubstituted cycloalkyl,R³⁶-substituted or unsubstituted heterocycloalkyl, R³⁶-substituted orunsubstituted aryl, or R³⁶-substituted or unsubstituted heteroaryl; R³⁶is independently oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,R³⁷-substituted or unsubstituted alkyl, R³⁷-substituted or unsubstitutedheteroalkyl, R³⁷-substituted or unsubstituted cycloalkyl,R³⁷-substituted or unsubstituted heterocycloalkyl, R³⁷-substituted orunsubstituted aryl, or R³⁷-substituted or unsubstituted heteroaryl; andR²⁸, R³¹, R³⁴, and R³⁷ are independently oxo, halogen, —CF₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCF₃, —OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl,unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstitutedaryl, or unsubstituted heteroaryl.
 2. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein L¹ is at least 17 Å inlength.
 3. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein the monovalent active site mTOR inhibitor is


4. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein the monovalent active site mTOR inhibitor is


5. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein the monovalent active site mTOR inhibitor is


6. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein the monovalent active site mTOR inhibitor is


7. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein the monovalent active site mTOR inhibitor is


8. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein L² is a R²⁶-substituted or unsubstituted 2 to 8membered heteroalkylene; L³ is a R²⁹-substituted or unsubstituted 5 to10 membered heteroarylene; L⁴ is a R³²-substituted or unsubstituted 2 to15 membered heteroalkylene; and L⁵ is a R³⁵-substituted or unsubstituted2 to 15 membered heteroalkylene.
 9. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein L² is 2 to 8 memberedheteroalkylene comprising at least one NH or 0; L³ is 5 to 10 memberedheteroarylene; L⁴ is —[(CH₂)_(b11)O]_(b12)—; L⁵ isCH₂CH₂C═(O)NH(CH₂)_(b10); b10 is an integer from 1 to 6; b11 is aninteger from 1 to 3; and b12 is an integer from 1 to
 8. 10. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein L² is—CH₂CH₂OCH₂—; L³ is triazolylene; L⁴ is —(CH₂CH₂O)_(b)—; L⁵ is—CH₂CH₂C═(O)NH(CH₂)₄; and b is an integer from 4 to
 8. 11. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, having theformula:


12. The compound of claim 1, or a pharmaceutically acceptable saltthereof, having the formula:


13. The compound of claim 1, or a pharmaceutically acceptable saltthereof, having the formula:


14. The compound of claim 1, or a pharmaceutically acceptable saltthereof, having the formula:


15. The compound of claim 1, or a pharmaceutically acceptable saltthereof, having the formula:


16. The compound of claim 1, or a pharmaceutically acceptable saltthereof, having the formula:


17. A pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and a compound of claim 1, or a pharmaceuticallyacceptable salt thereof.
 18. A method of treating a disease in a subjectin need thereof, said method comprising administering to said subject aneffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein said disease is a cancer, thrombosis,atherosclerosis, antiphospholipid syndrome, or stroke.
 19. A method oftreating a disease in a subject in need thereof, said method comprisingadministering to said subject an effective amount of a compound of claim1, or a pharmaceutically acceptable salt thereof, wherein said diseaseis a cancer.
 20. The method of claim 19, wherein said administering isthrough a drug-eluting stent.